^^
\ / .r ■ "'"*•
.#
^1^ vT -^^ % /
^"Afs
,s^ %
*^^i5:<■
.^^ ^^
^^ -^^
,<j^ ^^
^
?s ^.
/\^
^"^ .... 0d>. ^^^
% s^"^ <* ^sT <* ^^ % *r % <^^
■'"^ c?^ \, ""^
">>. .\r ^y ,sr ^y .n5^ 'yy. c^
.«,>, '■=%. .-#"" ^m:o ^<^
.<?^ \
\ ^'
..,. \. .# ...... \, j> -.,. %. .# ..,.,. %. ,# ..... %. .# ..,.,. \
Appendix
Research
on the
Fetus
The National Commission
for the Protection of
Human Subjects
of Biomedical and
Behavioral Research
This Appendix contains the
entire text of papers and reports
that were prepared for the Commission,
and certain other materials that were
reviewed by the Commission
during its deliberations.
U.S. Department of Health, Education, and Welfare
DHEW Publication No. (OS) 76-128
f
Mse-Tj(^ox,
NATIONAL COMMISSION FOR THE PROTECTION OF HUMAN SUBJECTS
OF BIOMEDICAL AND BEHAVIORAL RESEARCH
COMMISSIONERS
Kenneth John Ryan, M.D., Chairman
Chief of Staff
Boston Hospital for Women
Joseph V. Brady, Ph.D.
Professor of Behavioral Biology
Johns Hopkins University
Karen Lebacqz, Ph.D.
Assistant Professor of Christian Ethics
Pacific School of Religion
Robert E. Cooke, M.D.
Vice Chancellor for Health Sciences
University of Wisconsin
David W. Louisell, J.D.
Professor of Law
University of California at Berkeley
Dorothy I. Height
President
National Council of Negro Women, Inc.
Albert R. Jonsen, Ph.D.
Adjunct Associate Professor of Bioethics
University of California at San Francisco
Patricia King, J.D.
Associate Professor of Law
Georgetown University Law Center
Donald W. Seldin, M.D.
Professor and Chairman, Department of
Internal Medicine
University of Texas at Dallas
Eliot Stellar, Ph.D.
Provost of the University and
Professor of Physiological Psychology
University of Pennsylvania
Robert H. Turtle, LL.B.
Attorney
VomBaur, Coburn, Simmons & Turtle
Washington, D.C.
The Commission wishes to thanl< the members of its staff for the valuable assistance
provided in the study of research on the fetus and the preparation of this report.
COMMISSION STAFF
Charles U. Lowe, M.D.
Executive Director
Michael S. Yesley, J.D.
Staff Director
Professional Staff
Duane Alexander, iVI.D.
Edward Dixon, J.D,
Bradford Gray, Ph.D.
Miriam Kelty, Ph.D.
Robert Levine, M.D.
Barbara Mishlcin, M.A.
R. Anne Ballard
Bernice M, Lee
Support Staff
Mary K. Ball
Pamela L. Driscoll
Lisa J. Gray
Marie D. Madigan
Erma L. Pender
Susan F. Shreiber
Assistance was also provided by Charles McCarthy, William Dommel and Anthony Buividas.
CONTENTS
I. Reports and Papers Submitted to the Commission
1. The Nature and Extent of Research
Involving Living Human Fetuses Maurice J. Mahoney, M.D.
Principal Investigator
2. Fetal Research and the Value of Life Sissela Bok, Ph.D.
3. Fetal Research: An Ethical Appraisal Joseph F. Fletcher, S.T.D.
4. Balancing Obligations to the Living Human Fetus
with the Needs for Experimentation Marc Lappe, Ph.D.
5. Experimentation on the Fetus: Policy Proposals Richard A. McCormicl<, S.J.
6. Moral Issues in Fetal Research Paul Ramsey, Ph.D.
7. Experimentation on Fetuses Which Are Judged to be Nonviable Seymour Siegel, O.H.L.
8. Ethical and Public Policy Issues in Fetal Research LeRoy Walters, Ph.D.
9. Ethical Issues Involved in Experimentation
on the Nonviable Human Fetus Richard Wasserstrom, Ph.D.
10. Fetal Experimentation: Moral Issues
and Institutional Controls Stephen Toulmin, Ph.D.
11. Determining Death and Viability in Fetuses and Abortuses Leon R. Kass,N[.D., Ph.D.
12. Report on Viability and Nonviability of the Fetus Richard E. Behrman, LL.B., M.D.
and Tove S. Rosen, M.D.
Principal Investigators
13. The Law Relating to Experimentation w/ith the Fetus A. M. Capron, LL.B.
14. A Report on Legal Issues Involved in Research on the Fetus John P. Wilson, LL.B.
15. An Assessment of the Role of Research Involving Living Human Fetuses
in Advances in Medical Science and Technology Battelle-Columbus Laboratories
Critique of the Battelle Report Robert E. Cooke, M.D.
Commissioner
Response to the Cooke Critique Battelle-Columbus Laboratories
16. The Stability of the Decision to Seek Induced Abortion Michael B. Bracken, M.P.H., Ph.D.
CONTENTS (Continued)
II. Supplemental Resource Information
17. The Nuremberg Code of Ethics in IVIedical Research
18. Declaration of Helsinl<i
19. The Use of Fetuses and Fetal Material for Research, Report of the Advisory Group, Chaired by Sir John Peel,
London, 1972
20. Protection of Human Subjects: Policies and Procedures, Federal Register, November 16, 1973, DHEW
21. Protection of Human Subjects: Proposed Policy, Federal Register, August 23, 1974, DHEW
Part I
REPORTS AND PAPERS SUBMITTED
TO THE COMMISSION
THE NATURE AND EXTENT OF RESEARCH
INVOLVING LIVING HUMAN FETUSES
MAURICE J. MAHONEY, M.D.
Principal Investigator
Dr. Mahoney is presently Associate Professor
of Human
Genetics and Pediatrics at the Yale University School
of Medicine.
CONSULTANTS CONTRIBUTING TO THIS REPORT INCLUDE:
Harvey Bender, Ph.D.
Michael Kaback, M.D.
Associate Professor of Biology
Associate Professor of Pediatrics and Medical Genetics
University of Notre Dame
University of California at Los Angeles School
of Medicine
Norman Fost, M.D.
Associate Professor of Pediatrics
Bernard Mirkin, M.D., Ph.D.
University of Wisconsin School of Medicine
Professor of Clinical Pharmacology and Pediatrics
University of Minnesota School of Medicine
Fredric D. Frigoletto, Jr., M.D.
Assistant Professor of Obstetrics and Gyneco
ogy
LeRoy Walters, Ph.D.
Harvard University School of Medicine
Kennedy Center for Bioethics
Georgetown University
N01-CG-5-2112
The Nature and Extent of Research
Involving Living Human Fetuses
INTRODUCTION
The literature review is based on a National Library of Medicine (NLM)
MEDLARS search for published material reporting human fetal research. The search
matrix was designed by Ms. Charlotte Kenton at the NLM. We are indebted to her
and to other NLM personnel for their expertise and complete cooperation in gener-
ating literature materials. The NLM search covered the indexing years 1969-1974
plus a supplement for January 1975. The search was an all language search but
the review utilized only published material in English and other West European
languages, in Russian, or where English abstracts of East European and Asiatic
languages were available. We did not identify, via titles and indexing terms,
a significant literature in languages that were not surveyed. Supplementation
of the NLM search used major reviews for research prior to 1970, Biological
Abstracts (BIOSIS) , and Chemical Abstract Services (ACS).
A selected bibliography, primarily for the use of the Commissioners, which
emphasizes review articles or signal articles that highlight methodologies, is
made a part of this report. The extensive bibliography generated by the MEDLARS
search is available to the Commission through its staff.
Definitions
We have accepted as working definitions those advanced by the Advisory Group
to the Department of Health and Social Security, Scottish Home and Health Depart-
ment, under the chairmanship of Sir John Peel, in their report "The Use of Fetuses
and Fetal Material for Research," Her Majesty's Stationery Office, London, 1972.
These are:
Fetus : the human embryo from conception to delivery, without
distinction of an embryonic and fetal period.
Previable fetus: a fetus, with some signs of life, which has
not yet reached the stage at which it is able, and is
incapable of being made able, to function as a self-
sustaining whole independently of any connection with
the mother; the term is used for the human organism at
this stage in development whether inside or outside of
the uterus (contradicting the classic definition that
an organism outside of the uterus would no longer be
a fetus) .
1-1
Fetal death: the state in which the fetus shows none of the
signs of life and is incapable of being made to function
as a self-sustaining whole.
Fetal tissue : a part or organ of the fetus.
Fetal material: any or all of the contents of the uterus resulting
from pregnancy excluding the fetus, i.e., placenta, fluids,
and membranes.
Organization of Report
This report organizes the literature review in four broad areas:
1. Normal and abnormal growth and development of the implanted
fetus in utero
2. Diagnosis of fetal disease or abnormality
3. Fetal therapy and pharmacology
4. Research with the previable fetus outside the uterus.
It should be recognized that certain areas have been excluded from this
literature review. These are: (1) the fetus in utero before implantation or
the fetus outside of the uterus of comparable age (up to 7-10 days) ; (2) the
implantation process or research to interfere with implantation; (3) research
using the clearly dead fetus; (4) research with the extrauterine viable fetus
which we define as being synonymous with the premature infant. With regard to
the fourth item, we recognize the impossibility of operationally defining via-
bility in a strict sense, and have reviewed research with fetuses up to 28 weeks
gestational age that have signs of life outside of the uterus. Research with
fetuses in utero is reviewed through parturition.
LITERATURE REVIEW
Area One : Growth and Development In Utero
The primary purpose and rationale of anatomic and physiologic investiga-
tions of the human fetus is the obtaining of information concerning normal
developmental processes in order to understand the aberrant and ultimately to
meet the clinical aim of providing broad medical services to the fetus. At
the present time, although considerable basic information exists, much more
is required to be able to understand and treat the abnormal.' Developmental
information has been obtained through evaluation of each developing system at
various stages in gestation. Not infrequently, studies of the abnormal situa-
tion have catalyzed the investigations directly.
Over 600 publications were identified dealing with investigations of fetal
development and physiology. Close to half of these have defined anatomic param-
eters and the others have sought physiologic or metabolic information.
A. Anatomic Studies. Extrauterine dead fetuses and preserved fetal mater-
ials have been the most widely utilized systems for anatomic studies. These
have involved virtually all major tissues and organs, fetal membranes, and the
placenta. Techniques utilized include cytological, cytochemical , histological
and histochemical analyses of tissues at the light microscope and electron
microscope levels. X-ray diffraction and membrane studies utilizing optical,
thermal, nuclear magnetic resonance and spin-labelling techniques have recently
been employed. Detailed anatomic information regarding both normal and abnormal
growth and development of the fetus is available in several recent compilations.^"^
The anatomic definition of the human fetus at various stages of development
has, of course, required human material. Similar studies have been done with
other animal species and comparative information is available. The human studies
have used aborted fetuses from both spontaneous and induced abortions. For some
purposes, such as electron microscopic study of the brain, tissue must be obtained
very quickly after death. ^ In those instances, induced abortions (often hyster-
otomy abortions) are providing the fetuses.
B. Physiologic and Metabolic Studies. Living fetuses, live fetal materials
and preserved fetal material have been studied utilizing numerous experimental
approaches and sampling techniques which include: amniocentesis, amnioscopy,
angiography, maternal blood-fetal lymphocyte isolation, sonography, amniography,
fetography and fetoscopy. These techniques were often coupled with tissue cul-
ture and biochemical assays. Just as with anatomic studies, the majority of
investigations examining metabolism have used tissues excised from dead aborted
fetuses after similar studies with animal tissues. Some investigators have begun
the experimentation before or during induced abortion, often recovering chemicals
afterwards from umbilical cord blood or from tissues of the abortus . ^ Similar
studies have been done during caesarian section at term when a chemical is given
to the mother a few hours before operation and metabolic products are measured
in fetal umbilical cord blood at the time of delivery. i° Scalp blood has also
been used to measure a blood constituent before and during labor with vaginal
deliveries. ^^ These studies are low risk, nonbenef icial studies for the fetus
participating and have the aim of establishing normal fetal function so that
future fetuses in distress can be recognized and helped.
Other studies establishing normal data in the midtrimester human pregnancy
have measured fetal blood volume by injecting a chemical into an umbilical cord
vessel at the time of elective hysterotomy abortion, ^^ and have measured amniotic
fluid volume by injecting into the amniotic fluid just before abortion.!^ Amni-
otic fluid volume in later pregnancy has been measured at the time of amniocen-
tesis for Rh disease management or in normal term pregnancies when consent is
given solely for that purpose. Animal data exist for these parameters and the
studies are being done to establish normal data for the human as the basis for
improved fetal medicine. Many chemicals have been measured in amniotic fluid,
obtained for another indication, to establish normal data also.
Isolated organ culture using a tissue or organ from an aborted fetus has
given physiologic and developmental information about human organs after similar
studies in animals. Fetal muscle tissue is being examined in hopes of finding
1-3
leads to muscular dystrophy problems.^'' Fetal hearts, removed just after death
of a fetus following hysterotomy abortion, have been studied to establish phys-
iologic response data.^^-^^
C. Fetal Behavior. Some aspects of central nervous system development
have been studied via brain anatomy and brain metabolism in tissue from a
recently deceased fetus. Another approach has been to study behavioral phe-
nomena of the fetus in utero . Ultrasound has been used to document breathing
and gasping in animal and human fetuses (as early as 13 weeks), -^^ breathing
patterns change when a fetus is in jeopardy. Breathing has also been docu-
mented by injecting radiolabelled blood cells and radio-opaque dyes into the
amniotic cavity before the birth of deformed fetuses which were expected to
die soon after birth; the injected materials could be located in the lungs. ^^
Many studies have been done to document fetal hearing. A sound stimulus is
given through the maternal abdomen and a response noted by change in fetal heart
rate-'' or fetal electroencephalogram recorded from the fetal scalp or, earlier
in pregnancy, from the surface of the mother's abdomen.^" The nature of intra-
uterine noise has also been studied by inserting a microphone inside the uterus
before and during labor. ^'
Fetal movements have been recorded by deflections in an imposed electromag-
netic field and found to correlate well with a mother's sensation of movements. ^^
Taste has been inferred from rates of swallowing amniotic fluid after saccharin
or a radio-opaque dye was added to the amniotic fluid, 23 and vision has been infer-
red from a change in fetal heart rate when light was shined transabdominally . ^'i
Using movie films, the reflexes of previable fetuses outside of the uterus
have been documented along with the response of the fetus to touch. ^^ These
studies have shown a response to touch in a 7-week fetus, swallowing movements
in a 12-week fetus, and crying expressions at 23 weeks; the fetuses were studied
after hysterotomy while they were immersed in a salt solution.
D. Studies of the Pregnant Mother. Physiologic and pharmacologic studies
during pregnancy are also done with the mother. Reports only occasionally men-
tion effects in the fetus or say that effects were sought unless there was some
reason to believe there might be some problem for the fetus. The effects of insu-
lin and glucose infusions in the pregnant woman close to term have been studied ^6
to define the normal response in pregnancy and angiotensin II for blood pressure
response in pregnancy. ^^ Any responses of the fetus are generally unknown in
such studies.
Dietary changes during pregnancy have been the subject of a few studies.
The effects of wartime starvation on the fetus have been studied in retrospect,^*
and the benefit of nutritional supplementation on pregnancy outcome in deprived
populations has been cited. 29 Women undergoing elective midtrimester abortion
have been starved for 87 hours before abortion in an attempt to learn the effects
of caloric deprivation on pregnancy and to gain some information as to whether
the fetus could adapt to fuels other than glucose. 30 Extensive nutritional
1-4
experimentation has been done in animal species where significant detrimental
effects of nutritional deprivation have been demonstrated.
In general, attempts at defining growth and development in the human fetus
have followed the obtaining of similar information in animals. Some experiments
have been merely observational in nature while others have been invasive . Most
of the research is seeking data to benefit the field of fetal medicine and fetuses
as a class. Close to term, fetuses which will be born alive are involved; in
midtrimester , fetuses that will be electively aborted are often involved. The
risks are low for the fetus in most instances and the abortion process usually
is not prolonged.
Area Two: Diagnosis of Fetal Disease or Abnormality
A. Genetic Defects. Over 800 papers have been published in the scientific
literature since 1966 dealing with the detection of genetic defects in the human
fetus. These articles exclude those dealing with blood group incompatibility and
with lung maturation or fetal physiology.
The approaches used for the detection of genetic defects in the fetus have
included: (a) amniocentesis and the study of amniotic fluid or amniotic fluid
cells, (b) radiologic techniques including fluoroscopy, amniography, fetography,
(c) ultrasound, (d) fetal cells identified within the maternal circulation,
(e) fetal metabolites in maternal urine or, (f) most recently, direct endo-
scopic approaches including fetoscopy and/or fetal tissue or blood sampling
under direct observation. Three comprehensive reviews on these subjects have
recently been published .-''■^■^
This research has led to the current situation whereby virtually all cyto-
genetic aberrations of the human fetus can be detected by transabdominal amnio-
centesis, amniotic fluid cell culture and cytogenetic analysis. With recessive
genetic disorders, of the more than 100 disorders in man in which the specific
inborn metabolic error has been identified, approximately 60 of these can now
be detected by amniotic fluid cell study in vitro. ^"^ It is apparent from many
papers in the literature that inborn metabolic errors continue to be exponentially
identified and in so doing investigators are being greatly aided by the use of
somatic cell systems, particularly skin fibroblasts cultivated in vitro. Wherever
an inborn error has been identified in the cultured skin fibroblast system it has
been similarly studied in cultured amniotic fluid cells obtained from preabortion
amniotic fluid samples from otherwise normal pregnancies. This has enabled the
preliminary data to be derived from which the potential application to at-risk
pregnancies has been developed. Of the 50 inborn errors which are potentially
detectable by amniocentesis and amniotic fluid cell study, 23 of these disorders
have been successfully identified in at-risk pregnancies to date . ^^
Fluoroscopy, amniography, and fetography have been utilized for the identi-
fication of structural defects in the fetus including meningomyelocele, obstruc-
tive lesions of the gastrointestinal tract, genito-urinary abnormalities, bony
malformations involving the extremities, and anencephaly .^^'-^^ In addition, radio-
logic approaches have been applied to the detection of multiple pregnancies, and
1-5
have been uniformly employed as an adjunct procedure with intrauterine transfu-
sion. Such procedures have permitted investigations to be made of fetal and
placental circulatory dynamics through dye studies conducted immediately before
or after fetal transfusion.
In addition to this form of therapy (intrauterine transfusion) other thera-
peutic attempts have been made as an adjunct to amniocentesis. In particular
the intrauterine administration of hydrocortisone following third trimester
intrauterine diagnosis of adrenogenital syndrome has suggested the possibility
of treating this disease in utero from early in gestation.*"'*^ In two instances
an intrauterine diagnosis of galactosemia has led to selective dietary therapy
in the pregnant female through the remainder of pregnancy. On another occasion
diagnosis of vitamin Bj^2~^ssponsive methylmalonic acidemia early in gestation
led to therapy of the fetus for the last nine weeks of pregnancy by administering
huge amounts of vitamin 8^2 to the mother ."^ These few reports represent therapy
after diagnosis. They have all come in the last five years concomitant with the
application of fetal diagnostic attempts to identify genetic defects in early
pregnancy .
With the exception of the relatively few inborn metabolic errors where
therapy is an available alternative, the intrauterine studies which have been
done by amniocentesis or other methods have primarily been used as an adjunct
to genetic counseling in families at-risk for such disorders in their offspring.
Where amniotic fluid studies were performed in pregnancies not at-risk for a
genetic disorder, this was utilized as a method for ascertainment of normal levels
of biochemical parameters in cultured amniotic fluid cells and for determination
of culture methods for subsequent application to at-risk pregnancies. The basic
rationale in these studies has been to establish techniques for the prenatal
detection of genetic defects and to apply such information to at-risk families
as an improved form of genetic counseling. Prenatal genetic diagnosis enables
families at-risk for genetic disease in their offspring to obtain additional
information in a given pregnancy about that fetus. For the most part therapy is
not available for such disorders but if the fetus is found to be affected the
parents may elect to terminate the pregnancy by abortion as an alternative.
Conversely, where the fetus is unaffected they can be reassured and thereby have
unaffected children selectively. The goals of this work, in addition to obtain-
ing improved diagnostic skills, are repeatedly stated by many authors to be a
means of enabling at-risk families to reproduce without fear of often tragic
genetic disorders in their of f spring .^i-s"
Such studies have provided important information about the onset and early
pathology of genetic disease in the human fetus and to its detectability by such
indirect means as those indicated. An important offshoot of these studies has
been the acquisition of data related to the normal parameters of fetal biochemis-
try and development. The use of radiologic methods and particularly ultrasonic
techniques have provided important normative data concerning fetal growth and
development in utero.
The availability of a prenatal diagnostic method also has provided a basis
for the consideration of control of certain genetic disorders where they tend to
occur in particular high risk populations. Specifically the suggestion has been
made that consideration of amniocentesis and fetal cytogenetic screening in
pregnancies occurring in women over 35 years of age could result in a substantial
reduction in the incidence of Down's syndrome and other chromosomal aberrations,
nearly all of which lead to multiple abnormalities (mental retardation most
particularly).*'' In addition, the availability of prenatal detection methods
for certain inborn metabolic errors (where accurate carrier detection methods
are also available) has provided a basis for screening specific populations in
which particular recessive inborn metabolic disorders tend to occur, e.g., the
Ashkenazi Jews for the Tay-Sachs gene.** Carrier screening in the child-bearing
age group can permit the identification of couples at-risk for the disease prior
to the birth of affected offspring. Prenatal monitoring of all pregnancies in
couples so identified to be at-risk could achieve the prevention of births of
infants with disease (through selective abortion) and still enable such couples
to have unaffected offspring.
Although a number of investigators have used animal models (sheep, monkeys)
for amniocentesis and fetoscopy, each of these animal models offers major limi-
tations as a true model for the human situation. Accordingly, amniocentesis,
which was first developed in the 1930s as a technique for fetal monitoring for
blood group incompatibility between fetus and mother, has been extended to the
second trimester for genetic disease detection primarily through human experi-
mentation.
A number of genetic and ethical concerns have been raised regarding the
widespread application of prenatal diagnosis of genetic defects and selective
abortion. Several important articles and texts have been written on this and
related subjects .*5"*'
B. Rh Incompatibility Between Mother and Fetus. Articles were covered
which reflect a global experience with the diagnosis and management of fetuses
and pregnancies where Rh incompatibility is involved. Selected reviews are
referenced .*8'^°
The early introduction of amniocentesis in the 1930s as a means of monitor-
ing pregnancies at-risk for this problem has developed widely throughout the
world. Spectrophotometric determination on amniotic fluid supernatant has been
developed as an important technique for evaluation of the sensitized or poten-
tially sensitized pregnancy. In addition, the development of fluoroscopic and
radiologic techniques as an adjunct to intrauterine fetal transfusion (carried
out either by intraperitoneal or intracordal catheterization)^^ has been widely
reported. In essentially every instance, these methods have been employed in
pregnancies where clear evidence existed as to the dire prognosis for the fetus
unless some intervening action was taken. Accordingly these procedures were
carried out as potentially lifesaving procedures on a fetus who would otherwise
be severely jeopardized by the hematologic incompatibility. In a number of
instances additional experimental data was collected during the course of fetal
transfusion (fetal angiography and pylography) .
This area of therapeutic and clinical research has provided a basis for a
more expanded understanding of the hematologic interrelationships between the
fetus and mother and has provided a foundation for the development of techniques
1-7
for lifesaving procedures in certain specified situations. Moreover, the
development and experience with amniocentesis for this purpose provided the
basis for extending the procedure into earlier pregnancy for genetic disease
monitoring using amniotic fluid cells.
Through investigations related to Rh incompatibility, the role of fetal/
maternal hemorrhage in various stages of pregnancy (particularly in the period
surrounding delivery) and its relationship to maternal sensitization became
established. This led to the development and use of prophylactic anti-D immuno-
globulin for the prevention of Rh isoimmunization.
Throughout these investigative efforts, the judgement of the investigators
was that the risk for the fetus was greater than those risks envisioned or known
to be associated with the procedures. For example, the use of fluoroscopy and
diagnostic radiologic procedures as an adjunct to intrauterine transfusion,
although of some recognized risk to the fetus, was felt to be a much lower risk
than the risk to the fetus from the primary disorder for which the procedures
were conducted.
Studies in animal models have not been reported with specific regard to
Rh incompatibility. However, the extensive immunobiological data related to
immune tolerance and runt disease has been extensively studied in laboratory
animals .
C. Neural Tube Defects. In three years approximately 100 medical-scientific
publications have been published relating to the detection of neural tube defects
in the human fetus. ^^"^* The majority of these investigations have been conducted
in Great Britain and the United States. The preponderant direction of these
studies has been to develop techniques by which one could identify serious struc-
tural abnormalities of the neural axis (such as anencephaly and myelomeningocele)
either through visualization techniques such as roentogenography (with or without
radio-opaque substances introduced into the amniotic fluid), sonography, direct
fetoscopy, or by several biochemical determinations which could relate to such
abnormalities in the fetus.
Radiological procedures have primarily been applied to pregnancies in women
who have previously borne infants with structural abnormalities in the neural axis.
Using water soluble radio-opaque substances introduced into the amniotic fluid
after amniocentesis, this approach has been used to enhance the contrast within
the uterine cavity in order to better visualize specific structures in the fetus.
This technique, amniography, has been used also for the evaluation of fetal
gastrointestinal lesions since the fetus, in swallowing amniotic fluid, allows
the radiologist to view it's G.I. tract. With lipid solxible radio-opague sub-
stances introduced into the fluid, the chemical tends to adhere to the vernix of
the fetus and thereby outlines the outer perimeters of the fetus. This technique,
called fetography, has been successfully applied to the detection of several
structural abnormalities (phocomelia, meningomyelocele and anencephaly) in the
second and third trimester fetus.
Relatively recently it has been shown that in a number of situations where
neural tube closure is abnormal (leaving an open defect in the neural axis) ,
there is an elevation in the amniotic fluid alpha-fetoprotein level. Investiga-
tors in Great Britain, United States and Scandinavia have confirmed the finding
of elevated amniotic alpha-fetoprotein level in early pregnancy (10 to 20 weeks)
being associated with major structural aberrations of the neural tube. Elevations
of alpha-fetoprotein also have been found with gastrointestinal obstructive dis-
orders, with fetal death in utero, and with a few other serious fetal conditions.
Related research has demonstrated that in many such conditions the level of alpha-
fetoprotein in the serum of the pregnant woman may similarly be elevated. It has
been suggested that screening the maternal serum alpha-fetoprotein level between
10-20 weeks of pregnancy may provide a potential screening method for identifying
pregnancies with high risk for such structural aberrations in the fetus. Accord-
ingly the identification in the mother of elevated serum levels would be followed
by amniocentesis to assess the amniotic fluid alpha-fetoprotein level. This might
then be helpful in reducing the frequency of births of children severely afflicted
with such conditions (again implying selective abortion as an alternative) .
The primary rationale for these investigations has been to develop a method
for the accurate fetal diagnosis of serious structural aberrations in the devel-
opment of the neural axis. In certain parts of the world such abnormalities are
frequent (Wales, Ireland). Because the recurrance risk for such conditions in
families already having an affected child is between 4-6 percent the availability
of such techniques could be helpful in reproductive counseling of such families.
The interest in developmental biochemistry and fetal specific proteins has
been of considerable relevance to understanding of certain maturational processes
in the human organism. An important adjunct of these studies has been the handle
which some fetal proteins have provided for the study and detection of certain
kinds of cancer occurring in adulthood.
As such defects have only sporadically been identified in animal models there
has not been extensive study of such problems in animal models. The ethical ques-
tions raised by such investigations relate to the applicability of any test as a
screening method for the prevention (through abortion) of the birth of structur-
ally abnormal fetuses. . , , .,. .
D. Lung Maturity. Extensive studies have been reported in the literature
regarding the study of fetal lung maturation .55-57 in addition a number of papers
dealing with possible techniques to enhance lung maturation have been reported.
These studies primarily have considered the use of amniotic fluid obtained by
amniocentesis as a means to evaluate the lipid profile of the fluid (particularly
emphasizing sphingomyelin and lecithin determinations). Other studies designed
to monitor fetal respiratory movements in utero with ultrasonic scanning techniques
in the third trimester have also appeared. 58. 59 The latter has been proposed as a
potentially helpful means to evaluate fetal well-being and status in the latter
stages of pregnancy. The identification of respiratory movements and particularly
abnormal "gasping" movements in the fetus during labor or near term may prove to
be a critical and life saving new method in perinatal medicine.
The primary rationale behind such studies has been the development of tech-
niques to assess fetal maturation in pregnancies where intervention and premature
delivery might be considered. Particularly in pregnancies in which isoimmune
sensitization has occurred or in the diabetic woman, such information may have
critical importance. From these studies it has been established that with the
maturation of the fetal lung and the dynamics of amniotic fluid (fetal swallowing
and equilibration) increased concentrations of lecithin relative to sphingomyelin
in the fluid is a reflection of maturation of the fetal pulmonary system. This
has proven to be of considerable predictive value as to the likelihood of pulmon-
ary complications in the neonate. Obviously this kind of information has had
enormous impact on the management of certain high-risk pregnancies and has
reduced a major complication of premature delivery, pulmonary insufficiency or
respiratory distress syndrome. In addition this has given insight into the
developmental systems involved in lung maturation. In recent studies the intro-
duction of corticosteroids into the amniotic fluid has been reported to enhance
this maturation process. ^° This opens the possibility that when delivery is
indicated in a given pregnancy, assessment of fetal lung maturation can first be
made. Then if delivery must be carried out, some attempt can be made to enhance
the pulmonary maturation of the fetus before delivery.
Relevant animal research in this area has been conducted. Studies in the
rabbit and sheep have shown a maturational process with regard to the lung lipid
profiles and an enhancement of this process with the use of corticosteroids
introduced intra-amniotically . A major issue which has been raised about such
investigations is that the use of agents such as corticosteroids may have a
multiplicity of effects on the developing organism although only a single organ
system is the target for such therapy.
E. Fetal Weil-Being. In addition to many of the aforementioned studies,
a secondary value in all of these investigations has been the development of a
battery of information relating to determination of fetal well-being. Ultra-
sonic, radiologic, amniotic fluid and fetoscopic techniques conceivably do or
will relate to such an assessment. Accordingly all the data derived from amni-
otic fluid and from radiologic studies of the fetus in utero are important in
establishing data about the normal fetus at varying stages of pregnancy. This
is particularly true of techniques utilized in near term fetuses for the assess-
ment of fetal metabolic status through studies on fetal scalp blood samples .*'''®-^
Fetal electroencephalography has been evaluated in term fetuses and may prove
valuable as a means of evaluation of the status of the fetus at late stages of
pregnancy . ^^'^^
All of these studies also relate to the development of normative data about
the fetus and help to establish certain parameters by which to better evaluate
the fetus either in early pregnancy or near term. Consistently, these studies
have been carried out in an effort to enhance the pediatrician's or obstetrician's
capability to identify the threatened fetus (either from inherent, intrauterine,
or maternally related factors) so that appropriate avoidance methods or inter-
vention might be carried out.^^-^'
Such studies have provided considerable new information about the fetus
in utero. The respiratory movements and the growth and development of the
fetus as determined by ultrasound or radiographic techniques has provided impor-
tant normative data against which selected pregnancies can be compared. Such
data are extraordinarily helpful in assigning accurate gestational ages to fetuses.
This is of enormous importance in many pregnancies where the possibility of elec-
tive delivery is a consideration (isoimmunization, diabetes mellitus) .
1-10
In spite of the enormous data base that exists regarding fetal well-being
in the sheep and other laboratory animals, little of this is directly applicable
to the human situation. Anatomical peculiarities and physiologic differences
have meant that these models do not provide sufficient data necessary to answer
these questions in the human situation.
F. Effects of Amniocentesis. More than 100 papers in the 1959-1974 litera-
ture relate to the potential or actual hazards of amniocentesis .®®'^° The over-
whelming majority of these papers deal with anecdotal experiences, or case
reports or with sizeable series of pregnancies in which amniocentesis was uti-
lized in the third trimester to monitor for isoimmunization and/or fetal matura-
tion. Only a few papers are available dealing with complications of amniocentesis
during the second trimester. A major study carried out by the National Institutes
of Child Health and Human Development is currently being completed and within the
next six months an extensive report of this collaborative study, assessing the
risks of midtrimester amniocentesis, will be published. Although there potenti-
ally are a wide variety of immediate, short-term, or long-term effects of amnio-
centesis on the developing fetus, the reported experience to date concerning
both second and third trimester amniocentesis is extremely encouraging. There
has been minimal evidence of complications or deleterious effect on those fetuses
which have gone on to delivery. However these are primarily retrospective studies
and their design and completeness might be improved. It is hoped that the pro-
spective control study previously mentioned, and similar studies like it being
carried out in Canada and Great Britain, will more accurately resolve these ques-
tions. In addition to following pregnancies through to term each of these studies
involves an assessment of the offspring of those pregnancies through one or more
years after birth. This should provide some data about the long-term hazards of
amniocentesis. In the third trimester experience, the frequency of significant
complications with amniocentesis is also small considering that hundreds of
thousands of amniocenteses in later pregnancy have been conducted throughout the
world.
The emphasis in conducting such studies has been to ascertain the definitive
risk level associated with amniocentesis so that a more informed judgement could
be made both by the medical people involved and by families where this procedure
might be used on an elective basis. The potential value of amniocentesis and
the information it can provide must be balanced against the overall risk of the
procedure.
Such studies have provided additional basic information about the composition
of amniotic fluid, fluid dynamics, and the possible effects of such procedures on
certain complications such as fetal/maternal hemorrhage and isoimmunization.
Because of important biological, anatomical, and physiological differences,
no animal species has proven ideal as a model for human amniocentesis studies.
Difficulties in achieving pregnancy in certain animals in captivity, multiple
pregnancies, distinct anatomical differences in the type, location, size and
availability of the uterus and placenta, high spontaneous abortion rates in some
species, and a lack of adequate postnatal developmental milestones in most animal
species (in order to appreciate subtle long-term effects on psycho-behavioral
function and intelligence) are some of the major limitations to such studies.
G. Diagnostic Ultrasound Applications and Hazards. Between 100-200 papers
in the literature since 1958 are related to the use of diagnostic ultrasound in
pregnancy 7'"^^ As previously mentioned much of this work centers around the use
of ultrasound in both early and late pregnancy as a noninvasive method for ascer-
tainment of fetal status. In late pregnancy ultrasound has been used for assess-
ment of fetal respiratory movements as well as fetal maturation. Recent investi-
gations would indicate that the optimal method for evaluation of normal fetal
development in utero is the use of sonography to determine fetal head size and
growth. This is also the optimal means for determination of the gestational age
of the fetus. More recent studies have demonstrated that with advanced equipment
design (water coupled-grey scale sonography) , enormous detail concerning both
internal and external structure of the fetus can be ascertained in early preg-
nancy. In parts of Australia and Scotland, routine grey scale sonography or
B-mode sonography is conducted in early and late pregnancy as a means for assess-
ment of fetal maturation. Investigators in both countries have pioneered much
of the recent physical and engineering advances in this area. Studies in these
and other countries have demonstrated the enormous potential of ultrasonography
as a critical noninvasive instrument for the detection of structural abnormalities
of the fetus (anencephaly , meningomyelocele, congenital heart disease, congenital
renal disease) and as a vital instrument in the assessment of fetal well-being.
Such techniques have enormous and obvious potential importance for improved
obstetrical practice and for optimizing the management of pregnancy and the
newborn .
Similar studies in animal models have been conducted by numerous investiga-
tors and have demonstrated the distinct capability to visualize external and
internal structures of the fetus from very early stages of gestation through term.
The major concerns about ultrasonic diagnosis or diagnostic studies in preg-
nancy relate to the adequacy of studies concerning biological hazards of high
frequency sound. It should be noted that diagnostic ultrasound utilizes rela-
tively low frequency, short duration, sound pulses and with newer equipment the
exposure may even be reduced further.
The potential hazards of ultrasonic exposure to the fetus have been con-
sidered by numerous investigators. The entire July 1972 edition of the British
Journal of Radiology is devoted to this subject. Experiments in plants, bacteria,
and animal models (with the level of intensity utilized for diagnostic ultrasound
in human pregnancy) have not been associated with any clear or obvious deleterious
effects. Preamniocentesis ultrasonic B-mode scanning for placental localization
is now widely practiced throughout this country as a routine part of this diag-
nostic procedure. Professor Ian Donald's group in Glasgow, Scotland, has probably
had the longest experience with ultrasound use in pregnancy. This group has
recently evaluated a substantial number of Glasgow children who were exposed as
fetuses to ultrasound as many as seven or eight years previously. No evidence
of hearing deficit or developmental abnormality could be identified in this
substantial series of school children.
While a number of questions may still remain unanswered as to the potential
hazards of diagnostic ultrasound in pregnancy, no evidence exists at this point
in either animal, plant, or human species indicating any clear evidence of hazard.
On the other hand the demonstrated value of ultrasonic utilization in certain
pregnancies and the potential use of this technique in practically all pregnancies
(particularly for gestational age determination and assessment of fetal well-being)
are already obvious.
H. Diagnostic X-Ray of the Fetus. The diagnostic use of X-ray and related
procedures in pregnancy has been widely reported.'^ Pelvimetry and assessment
of multiple pregnancy by radiologic technique is recognized and established
obstetrical practice. In addition, radiologic techniques have been utilized in
selected pregnancies where concern regarding bony or structural abnormality of
the fetus was an issue. In addition, as previously mentioned, radiologic tech-
niques have been extensively utilized as an adjunct to intrauterine transfusion.
The associated use of radio-opaque materials for amniography or fetography have
also been implemented in pregnancies where structural anomalies of the fetus
were suspected or as an adjunct to intrauterine fetal transfusion.
Such techniques have been applied in full recognition of the biological
hazards of X-radiation. In every instance it was regarded that the benefits to
be gained by utilization of X-ray techniques outweighted the risks associated
with the exposure of the fetus.
Extensive bacterial, plant, and animal investigations have been conducted
regarding the hazards of X-ray exposure. The teratogenic, carcinogenic, muta-
genic and cell replication effects of X-ray have been characterized in lower
forms and have been consistently associated with doses of X-ray exposure con-
siderably in excess of those utilized in the aforementioned procedures. However
there are certainly considerations regarding the zero threshold for deleterious
effects of X-ray with any experimental or procedural activity regarding the fetus
and X-ray should be avoided whenever possible.
I. Fetal Cells in Maternal Circulation. Relatively little information is
available on this approach to intrauterine fetal study as yet. It has been
reported in several publications that throughout pregnancy a small amount of
fetal blood is introduced into the maternal peripheral blood. '^ Investigators
have recently demonstrated that lymphocytic cells in addition to red blood cells
can be identified in maternal peripheral blood in small numbers. This has
enabled identification of male fetuses from karyotypes prepared from peripheral
blood samples obtained from the mother. One important limitation in this
approach is that lymphocytes from the fetus apparently "colonize" in the mother
and remain there for substantial periods of time. As long as two years after
the birth of a male fetus, cytogenetic analyses of maternal peripheral blood
have been reported to still show small numbers of male 46XY cells. This is a
rather remarkable phenomenon and merits further investigation. Obviously such
techniques are not applicable as yet to the study of the female fetus. However,
it may be possible with further study that a technique to selectively isolate
leukocytic, lymphocytic or erythrocytic cells could enable investigations to be
carried out on selected fetal cells derived from the peripheral blood of the
mother. Certain immunologic and cell size differences between fetal and maternal
cells may prove helpful in such an isolation procedure. Further research is
being conducted in this regard.
1-13
This approach would be most appealing. The concept that a peripheral blood
sample obtained from a pregnant woman would provide the medical scientist with
selected cells of fetal origin would have enormous potential for fetal diagnosis.
Other considerations along these lines, involve the potential use of maternal
urine samples to assess certain metabolic parameters in the fetus. The estab-
lished use of estriol determinations in maternal urine as a measure of fetal
well-being has been well substantiated by many investigators, and is an example
of such an approach. Certain inborn metabolic errors might also prove detectable
in the fetus with such approaches.'*
J. Fetoscopy ■ Another new approach to diagnosis in fetal medicine is
endoscopic viewing within the uterus and the biopsy of fetal tissues, especially
of fetal blood .^'''^ This technique was developed with women undergoing midtri-
mester elective abortion and holds great promise for significantly widening the
scope of fetal diagnosis of both genetic (e.g., hemoglobinopathies) and acquired
disease (e.g., growth failure in utero) ; the technique should also allow the
development of therapies which would have to be monitored by a skin or blood
sample from the fetus. Clinical application is just starting. Three fetuses
at risk for beta-thalassemia have been correctly diagnosed as free of the disease;
fetoscopy was used in one of the pregnancies and direct placental aspiration of
fetal blood in the other two.
Accurate diagnosis must be the basis for all medical considerations, whether
it be treatment, correction, prevention, or intervention. Although much of the
research to date has been directed primarily toward diagnosis, this must be the
first step if effective treatment, cures, or prevention are to be ultimately
achieved.
Area Three: Fetal Therapy and Pharmacology Which Has Involved the Living
Human Fetus
A. Developmental Pharmacology. A precise, quantitative determination of
how many studies have been carried out in the area of developmental pharmacology
is virtually impossible to achieve. One of the major reasons for this is the
difficulty encountered in clearly distinguishing prima facie studies directed
toward assessment of drug action in the human fetus from those which may become
research studies by secondary intent, a posteriori so to speak, e.g., where a
pharmacologic agent has been utilized to manage a specific therapeutic situation
in a pregnant woman resulting in some pharmacologic effect upon the fetus or
neonate .
From the current literature search, approximately 400 publications dealing
with fetal pharmacologic research were identified, and about 70 of these fit the
criteria of human fetal research which we have adopted. These data indicate that
a rather broad spectrum of pharmacologic agents has been studied in the human
fetus. The relative frequency of publications in specific areas of developmental
pharmacology has been summarized in Table 1. This information is quite intriguing,
1-14
since it clearly suggests that a majority of investigations in this area are
merely appendages to clinically acceptable therapeutic procedures performed
during the prepartum (early and late) or parapartum phases of pregnancy. In
this regard the overwhelming majority of studies were carried out close to
parturition or during the parapartum period.
Table 1. Pharmacologic Investigations Involving the Living Human Fetus*
(Frequency Distribution of Studies Published from 1969-1974)
Item
Number
Drug Investigated
Anesthetics and Analgesics
a. Obstetrical anesthesia
b. Local anesthetic; placental
transfer, fetal effects
Cardiovascular Agents
( 3-adrenergic agonists; atropine,
prostaglandin)
Number
of Studies
24
(13)
(11)
Percent
of Total
33
(18)
(15)
9
10
Oxytocic Agents
(Effect on fetal acid base balance;
uterine perfusion)
Hormones
(Oral contraceptives, insulin, thyroid)
Anti-infective Agents
(Antibiotics, quinine, chloroquine)
Anticonvulsants
Antineoplastic Agents
Drugs of Abuse
(Addicting agents, morphine, alcohol)
Diuretics
Psychopharmacologic Agents
13
*This table illustrates the broad spectrum of drugs and problems investigated.
It is not intended to be all inclusive and some studies performed during the
period 1969-1974 are omitted.
1-15
With the exception of a very few published investigations, research involving
the assessment of drug action in the human fetus has utilized techniques which are
generally noninvasive and/or low risk in nature. The procedures which have been
employed are categorized beljw:
( 1 ) Invasive or Potentially Harmful Procedures;
a. Amniotic fluid sampling.
b. Scalp vein sampling at the time of parturition.
c. Fetal blood sampling obtained by fetoscopic techniques (this
procedure has not been utilized for any fetal pharmacologic
studies as yet; however it presents a major tool for the
future) .
d. Prepartum fetal blood transfusions containing drugs.
e. Drugs administered to the mother for therapeutic reasons or
for the purpose of studying placental passage and fetal dis-
tribution patterns. (While such investigations generally
are carried out in individuals terminating pregnancy by
abortion, some studies have been performed in which placental
transfer was determined in normal pregnancies at the time of
parturition . )
(2) Noninvasive and Minimal Risk Procedures:
a. Fetal electrocardiogram.
b. Ultrasonic detection of fetal structures and movements.
c. Analyses of umbilical cord blood (studies have been carried
out in Sweden during which radioisotopes were injected into
the fetus while it remained in situ and connected to the
placenta for relatively prolonged periods of time. Blood
specimens were obtained from the umbilical vessels and fetal
steroid biosynthesizing capability estimated) .
(3) Isolated Tissue Studies:
a. Tissues are generally biopsied after fetal death (cessation
of spontaneous respiration and heart beat) and utilized to
study drug metabolism in vitro.
B. Major Objectives and Rationale for Research in Developmental Pharma-
cology Involving the Living Human Fetus. The human living fetus has seldom,
if ever, been used for the exclusive purpose of determining what specific
pharmacodynamic actions a drug may exert upon the fetus or its physiologic
maintenance systems. The rationale for research studies and protocols in devel-
opmental pharmacology evolve from several major information deficits regarding
1-16
drug action on human development. In general, the need for specific types of
data has provided the stimulus for discrete investigations in the human; as such,
objectives, and perhaps rationale, vary in a temporal sense, according to the
stage of gestation under scrutiny:
(1) Drugs Administered Prepartum:
a. Agents Used Early in Pregnancy: Virtually no preconceived
research in the living human fetus has been carried out with
agents falling into this category, and retrospective studies
are the general rule. If compounds administered prenatally
are observed to produce untoward effects on fetal development
or neonatal survival, then a stimulus for studies in the human
is provided; if not there is seldom further inquiry. Studies
of this sort always occur after the fact or are a posteriori
in nature.
Examples are quite common and drugs currently being discussed
are the (1) oral contraceptives and the potential influence
that they exert on twin births and the production of congenital
defects (heart and limb); (2) drugs of abuse such as morphine
and methadone which may produce addiction and withdrawal symp-
toms in the neonate. It is surprising that virtually no
pharmacodynamic studies on the latter question were initiated
until 1965 considering that the symptom complex was clinically
observed and well documented in 1930.
Another aspect of this overall problem is related to the uti-
lization of over-the-counter medications by pregnant women.
It is virtually impossible to establish any meaningful data
regarding the potential hazards of such compounds and there
appears to be no regulatory requirement necessitating that
the potential hazards of such drugs be assessed in pregnant
women prior to their utilization ."^5. so
b. Agents Used in a Medically Accepted Manner for the Treatment
of Maternal Illnesses: The unanticipated effects of compounds
employed in the management of intercurrent maternal illnesses
during pregnancy provides a major impetus for many investigative
studies. Many illustrations of this phenomenon exist and some
of the more significant examples are cited below:
Classification Specific Agent Reference
Anti-infectives Antibiotics, Antimalarials 81-85
Hormones Thyroid, estrogens, progestins, oral 85-90
contraceptives
Antineoplastic Ethambutol, cytosine arabinoside 91-93
Immunosuppressive 6-MP
Anticonvulsants Diphenylhydantoin, phenobarbital 94-96
Drugs of abuse Morphine, alcohol 97-98
Local anesthetics Mepivacaine 99-100
(2) Drugs Administered Parapartum:
a. Agents Used to Facilitate Delivery: The compounds in this
general category (analgesic agents and anesthetics) are
probably the only major classification of drugs which have
been extensively investigated in the human maternal/placental/
fetal unit, at least by primary intent. An important force
in this respect appears to be the societal pressures placed
upon clinical obstetrics to produce a safe, relatively pain-
less birth by use of drugs which exert minimal influences
upon fetal and neonatal viability and development. In
consequence thereof, numerous new anesthetic procedures and
agents have been extensively investigated in the living human
fetus, primarily at the time of parturition (see Table 1).
C. Nature and Relevance of Information Obtained from Pharmacologic Investi-
gations in the Living Human Fetus. Despite the difficulties encountered in
designing studies for the assessment of drug effects in pregnant women and on
the fetus, a surprisingly broad range of problems in developmental pharmacology
has been investigated. Among the most significant of these are the following:
(1) Placental Transfer and Fetal Disposition of Drugs:
a. Data describing which drugs cross the placenta, their relative
rates of passage, the amount of drug reaching the fetal circula-
tion after maternal administration, and the influence of modifi-
cations in molecular structure upon these parameters has been
obtained. The disposition of maternally administered drugs in
the fetus has been studied indirectly by analyzing tissues
obtained shortly after fetal death.
b. The relevance and application of these data to the treatment
of fetal disease can be identified in many areas:
1. Knowledge regarding placental drug transfer is crucial
for the proper selection of antibiotics in the treatment
of intrauterine infections of pregnancy.
2. Studies relating molecular configuration, physical chemical
properties and placental transfer may allow the develop-
ment of drugs for use specifically in pregnant women (i.e.,
agents whose pharmacodynamic effects will be exerted in the
maternal organism for treatment of maternal illness with no
effects on the fetus). Contrariwise, if the problem involved
the maternal/placental/fetal unit, it may be possible to
modify drugs so that they are able to enter the fetal circu-
lation and exert appropriate effects therein.
3. The development of fetal drug therapy (e.g., digoxin admin-
istration with intrauterine blood transfusions) requires
data describing the most efficient way to administer drugs
to the fetus. It may be possible to administer drugs to
the mother and achieve therapeutically effective blood
levels in the fetus without the potential hazards of intra-
uterine fetal drug administration. In a similar manner,
certain drugs can be instilled into the amniotic fluid
compartment to achieve therapeutically effective concentra-
tions in the fetus .
4. Understanding the nature of fetal distribution is important
since it determines how much drug will reach a given fetal
organ and potentially modify normal physiologic functioning.
Fetal blood circulation exerts a major effect on fetal drug
metabolism by selectively shunting drugs through the liver
(via the ductus venosus) thereby preventing biotransforma-
tion by this organ during the initial circulation of the
drug.
(2) Drug Disposition in the Maternal/Placental/Fetal Unit:
a. The fetal metabolism of drugs has been studied through virtu-
ally the entire phylogenetic range of mammals. It is start-
ling to note that the human fetus differs remarkably from the
subhuman in that appreciable metabolism of drugs and other
xenobiotic agents can be detected within the first trimester
of pregnancy. Numerous studies on the metabolism of drugs by
fetal tissues (e.g., liver, placenta and kidney) excised from
dead fetuses have been carried out in order to confirm these
particular characteristics of the human. There is still minimal
data describing drug metabolism in the maternal/placental/fetal
unit under in vivo conditions, so that at the present time it
is difficult to state the physiologic importance of these obser-
vations.
b. The studies on drug metabolism by isolated tissues have partic-
ular relevance in that these data suggest the fetal liver has
the capacity to form specific toxic products which are known to
be noxious to biological tissues. The important question which
arises is whether these metabolic by-products are responsible
for causing the teratologic effects produced by many drugs.
Investigations of drug metabolism in the fetus are also important
for the information they provide regarding enzyme induction at
different stages in development, with particular emphasis on
the role it may play relative to enhancing neonatal survival.
Thus, the action of inducing agents (e.g., phenobarbital) or
the effects of environmental pollutants (e.g., DDT) upon enzyme
systems suggests that some important physiologic processes can
be stimulated by exposure of the fetus in utero to specific
drugs (e.g., phenobarbital and increased conjugation of bili-
rubin). The response of the fetus to certain drugs of abuse,
such as the addicting analgesics, is important to understand
since addiction and withdrawal symptoms have been described in
the fetus in ever increasing numbers.
1-19
(3) Drug Effects on Specific Physiologic Processes Unique to the Maternal/
Placental/Fetal Unit:
a. Agents Acting on the Cardiovascular System: The response of
the umbilical and placental circulations to a variety of vaso-
active drugs has been studied in detail. Many of these agents
have been used to inhibit uterine motility, particularly during
premature labor, and as such are also able to exert marked
effects upon vascular smooth muscle. Data regarding placental
blood flow and alterations in oxygen diffusion are crucial if
these agents are to be used as standard therapeutic procedures
at the time of parturition.
Not only can vasoactive agents modify diffusion and transfer of
substrates across the placenta, but if these compounds are able
to enter the fetal circulation in effective concentrations,
they may significantly alter drug distribution within the fetus
itself, perhaps in a manner which may be deleterious to survival.
Thus it is important to distinguish the effects of such agents
upon the distribution of fetal cardiac output since local alter-
ations in blood flow may exacerbate fetal distress or decrease
neonatal survival.
b. Agents Acting on the Endocrine System: The fetus and placenta
act in a synergistic manner with regard to endocrine function
' during gestation. The products produced by this integrated
unit are essential for fetal survival, and it is extremely
important to identify how these processes may be influenced by
drugs. Not only must interrelationships between fetus and
placenta be considered, but maternal and fetal interrelation-
ships relative to organs like the thyroid gland and the produc-
tion of thyroid hormones, the kidney and the production of
renin and the adrenal gland and the production of adrenocortical
hormones must be considered in response to maternal hormonal
changes and any drug therapy the mother may be receiving.
In this regard it is worth noting that treatment of maternal
hyperthyroidism with goitrogenic agents may lead to neonatal
goiter; administration of insulin to the mother may so lower
maternal blood glucose levels as to initiate responses to this
hypoglycemic stress on the part of the fetal pancreas and fetal
sympathetic nervous system. Also, changes in placental perfu-
sion with alterations in fetal blood volume may cause secretion
of renin from the fetal kidney in order to maintain homeostasis.
Any pharmacologic agents which modify or alter the processes
described above can significantly influence fetal well-being.
D. Alternative Methods for Predicting the Effects of Drugs on the Human
Living Fetus. A substantial amount of information regarding the pharmacology
of the maternal/placental/fetal unit has been derived from studies on experimen-
tal animals, particularly subhuman primates (baboons, monkeys), ovine species
(sheep, goat) and rodents (rats, guinea pigs). Quite obviously the selection
of an animal species for any given study is dependent upon the problem to be
investigated, and this will vary for each particular system under study.
1-20
It is extremely difficult to predict whether observations made in a particu-
lar animal species will have relevance with regard to the human maternal/placental/
fetal unit. Several examples are cited below:
(1) The fetal distribution of drugs may differ between species. Thus,
the tissue localization pattern of diphenylhydantoin in the mouse,
rat and human is similar; whereas, that of digoxin differs markedly
in the rat in comparison with that observed in the sheep or human
where it is virtually the same. .^ ■
(2) The matabolism of drugs by the human fetal liver is different
from that which occurs in fetal tissue obtained from other mam-
malian species. In particular it has been shown that many
oxidative activities are barely detectable in tissues obtained
from fetal or newborn animals , whereas human fetal liver is able
to metabolize appropriate drug substrates to a significant extent.
Indeed, observations in subhuman species have been misleading
with respect to identifying events occurring in the human fetus.
(3) The study of placental function in the human is obviously best
undertaken in that species; wherever this is not feasible some
subhuman primates may be acceptable. Ironically, a large amount
of our information on placental function is derived from observa-
tions carried out in the sheep and its fetus, which may have very
significantly different drug transport characteristics when com-
pared with the human. It is always questionable whether general
principles enunciated in such experimental models have validity
for the human. For this reason it is imperative that extensive
investigations be carried out in order to identify those subhuman
models which are most appropriate for predicting a given pharmaco-
logic effect in the human, if models can be found.
E. Live Virus Vaccines. A few viruses are known to cause disease in the
human fetus. One of these is rubella (German measles) for which an attenuated
live vaccine was recently developed. Studies were designed to learn whether
the vaccine virus would invade the fetus after negative answer to that question
in monkeys . Women who requested abortion were asked to accept vaccination and
to postpone abortion for 3-4 weeks. In one study two previously immune women
declined abortion after the vaccination. ^°' These studies have shown that the
vaccine virus can infect the fetus. A similar study has been done with attenu-
ated mumps virus; abortion was 7-10 days after vaccination and virus was recovered
from the placenta but not the fetus. 102 These studies have emphasized the dangers
of attenuated virus vaccines for pregnant women.
F. Therapeutic Abortion. Efforts to develop new methods or agents to
terminate pregnancy have been oriented toward maternal safety. ^"-^ We have found
no evidence that these studies concern themselves with fetal considerations.
The recent development of the prostaglandins as midtrimester abortif acients has
produced a method which is less destructive to the fetus than the previously
used saline injections. This was fortuitous, however; maternal safety was the
major impetus.
1-21
Area Four: Research With the Previable Fetus Outside the Uterus
An immediate problem that arises in analyzing extrauterine research on
previable infants concerns the definitions of living and dead fetuses. Distinc-
tions must be drawn between organism death, organ death, tissue death, and
cellular death. The vast majority of reported research on the extrauterine pre-
viable fetus involves fetuses which are clearly dead as organisms, be the criteria
cardiac, respiratory, or brain death. There are many therapeutic and research
uses for tissues from dead fetuses. After death of the whole fetus, many tissues
continue to live for a considerable period of time. They are used for tissue and
cell culture, for transplantation into defective living persons, and for studies
of metabolic and cellular function. Tissue cultures from human fetuses have
become indispensible for the growth of certain human viruses and the development
of viral vaccines. The dead fetus is also used in completing studies that have
commenced while the fetus was still alive in utero. Thus, pharmacologic studies
investigating placental transfer of a drug or distribution of a drug in fetal
tissues require recovery of the fetus after it has been delivered. Similar
requirements have been present to learn whether a virus has infected a fetus
before delivery.
Research on fetuses outside of the uterus that have signs of life may be
classified according to the degree of intervention with the fetus. For example:
(1) Chart Research. This would be the least hazardous research on
previable, living infants, consisting of retrospective analysis
of data already recorded for other purposes, such as anthropo-
metric data, malformations noted while still alive, presence and
duration of signs of life.
(2) Observation Research. Prospective studies may involve only
looking or measuring. This would include pure inspection,
without altering the infant's environment for the purposes of
study. Slightly more intervention would include mild manipu-
lation, such as occurs to collect anthropometric data. Moni-
toring with instruments such as EEG, X-rays, radioisotope
scans, would involve further manipulation.
(3) Collection of Body Fluids and Tissue. These would range from
simple samples such as urine, hair, fingernails, to blood
samples obtained by fingerstick or venepuncture, to secretions
from nasopharynx, trachea or stomach, to cerebro-spinal fluid.
Tissue collection might include biopsies, such as skin or
brain, or removal of whole organs.
Research on the previable fetus is often done with protocols which are also
being applied to a viable fetus or premature infant. At the time of the research
it is not known whether the fetus has the potential to achieve independent life.
Thus, many of the therapeutic modalities and- research efforts of modern neona-
tology that have been applied to the premature infant have also been applied to
larger previable fetuses. With these fetuses, there is no clear distinction
between fetal research and neonatal research. The research is meant to be either
beneficial to the sxibject or is a minimal intervention that would not limit the
opportunity for the subject to achieve viability.
Research with living previable fetuses outside of the uterus has not been
extensively reported in the medical literature. The studies listed below repre-
sent all those found in reviewing the more than 3,000 citations in the literature
research.
(1) Studies in other species and in adult humans had indicated that
the brain could utilize other substrates than glucose for fuel.
Also, ketone bodies appear in the mother's blood stream and in
amniotic fluid during starvation.^" To learn whether the human
fetal brain could metabolize ketone bodies, brain metabolism was
isolated in 8 human fetuses (12-17 weeks' gestation) after hyster-
otomy abortion by perfusing the isolated head (the head was
separated from the rest of the body) . The study demonstrated
that, similar to other species, brain metabolism could be sup-
ported by ketone bodies during fetal life suggesting avenues of
therapy in some fetal disease states. ■'°*
(2) Endocrine functions of the placenta and fetus combine to support ' ■.
the maintenance of a pregnancy and the growth and maturation of
the fetus. To study the fetal endocrine system, arginine (an
amino acid) was injected into a blood vessel in the neck of 8
human fetuses (450-600 grams) while the umbilical cord and placenta
were still attached to the uterus. Blood samples were taken from
the umbilical cord to yield information about fetal endocrine
regulation. i°5
(3) Another technique for studying the ability of the midtrimester
fetus to carry out endocrine reactions used 4 fetuses (16-20
weeks' gestation) immediately after hysterotomy abortion. The ; ;
fetuses were perfused through their umbilical veins while being
housed in a perfusion tank. Fetal tissues were examined at the
end of the study. The study showed that the fetus alone, inde-
pendent of the placenta, could snythesize estriol, an important
compound in assessing fetal and placental health in later preg-
nancy.'"*
(4) Amino acid levels are low in malnourished children and adults.
To learn if this were true in newborns that had been malnourished
in utero , blood samples from a peripheral vein were taken to
measure amino acid concentrations. This study was done in
infants, most of whom were older than 28 weeks' gestation so
that only a few were likely previable.'"'
(5) Another study that represents neonatal research more than research
on the previable fetus used the umbilical vein to measure total
body water (bromide space) in low birth-weight newborns. This
study also suggested that changes in prenatal malnutrition were
similar to those in postnatal malnutrition.'"^
1-23
(6) Some studies which use umbilical cord blood are completely
noninvasive for the newborn (previable fetus or viable pre-
mat' 2 infant) . One such study measured hemoglobin in cord
blood to learn if there was a correlation with maturity.^"'
A few studies with the previable fetus have made att'^mpts to
supp 'rt life in novel ways that might eventually allow similar
fetuses to achieve viability or might be methods for treating
premature infants with otherwise fatal respiratory distress
syndrome. These studies are part of attempts to develop an
artificial placenta. The life of the previable fetus was pro-
longed (death was delayed) in some instances.
(7) After studies with newborn and fetal mice, cutaneous respira-
tion (breathing through the skin) was studied in 15 fetuses
(9-24 weeks' gestation) from induced abortions. The fetuses
were immersed in a salt solution with oxygen at high pressure.
The fetuses were judged to be alive by a pulsating cord or
visible heart beat; if necessary the chest was opened to
observe the heart. Four fetuses were supported for 22 hours
in this attempt at developing a fetal incubator . ^■'°
(8) Seven previable fetuses (200-375 grams) from spontaneous or
induced abortions were immersed in a perfusion tank and per-
fused with oxygenated blood through their umbilical vessels.
The fetuses survived and moved for 5-12 hours. ^^■'
(9) After considerable work with rabbits, a similar experiment was
done with perfused, oxygenated blood with 8 fetuses (300-980
grams) after hysterotomy abortion. If perfusion was stopped
early, the fetus could live only about 20 minutes; continuous
perfusion enabled maximum survival of 5.1 hours. ^i^
(10) Following opening of the uterus for hysterotomy abortion, a
segment of umbilical cord was exteriorized and blood samples
were obtained from it for 10-15 minutes. Studies were attempted
in 38 cases, at 14-2 3 weeks' gestational age. The study pro-
vided a model for obtaining data from the human midtrimester
fetus without additional hazard to the mother. ^'^
(11) Labeled noradrenaline was injected into either the umbilical
vein or jugular vein of the fetus while the placental circula-
tion was kept intact for 15 minutes. Metabolites were assayed
in various fetal tissues following completion of the abortion.
The study demonstrated activity of the fetal sympathetic nervous
system early in gestation.^-''* In a similar study, radiolabeled
testosterone and testosterone sulphate were injected into a
15 week and a 16 week fetus during hysterotomy abortion. The
products of conception were removed 15 minutes later, and metab-
olites analyzed in tissues of the dead fetus to study fetal
hormone synthesis and metabolism. iis
(12) In a study to develop methodology for research in fetal physi-
ology, intact fetoplacental units at 15-19 weeks' gestation were
transported to the laboratory, immersed in artificial amniotic
fluid, and perfused via an umbilical catheter.'*®
(13) Ten fetuses of 20-24 weeks' gestation had carotid artery cannu-
lations following hysterotomy abortion to study the relation- ,
ships between growth hormone, plasma glucose, and stress in the
fetus or premature infant .i*' .. . . ,
(14) Six fetuses (15-20 weeks' gestation) were perfused via the umbil- ;
ical vein immediately following hysterotomy abortion. Studies
following injection of labeled progesterone showed that the fetus
could utilize progesterone for male steroid hormone manufacture .*'*
The above experiments with previable fetuses were all extending previous
animal work to the human situation. The experiments vary widely in invasiveness
for the fetus. When the fetus was clearly previable, the research was not bene-
ficial for that subject but was seeking information that could be of benefit to
other fetuses.
SUMMARY OF LITERATURE REVIEW ":■■
Our literature review has revealed extensive research in fetal medicine
from all parts of the world during the past ten years. Several thousand reports
have been published in that period. A large percentage of this effort has been
directed at identifying the threatened fetus in utero , especially in later
pregnancy and during labor, and devising methods to successfully manage fetal
problems. There have been major changes in obstetric practice which involve
monitoring of the fetus and concomitantly a significant decrease in perinatal
mortality. In recent years there has been increasing attention to the fetus
earlier in gestation with major efforts being made to evaluate maturity
(expecially lung maturity) and readiness for extrauterine life and to diagnose
fetal abnormalities and disease. Diagnostic capabilities, most notably through
the use of amniocentesis and ultrasonography, have progressed rapidly. Thera-
peutic possibilities are just beginning to be developed. One major consequence
of increasingly sophisticated fetal diagnosis has been decision making in mid-
pregnancy resulting in selective abortion of fetuses with various abnormalities.
For the most part, knowledge that has resulted in improved diagnosis and
therapy for the fetus has been developed in continuing human pregnancies where
there has been beneficial intent toward the fetus. There have also been obser-
vations in parallel on normal pregnancies. When diagnostic or therapeutic
interventions have been made, such as amniocentesis or fetal transfusion, oppor-
tunities have been recognized for obtaining unrelated data at minimal risk to
that fetus or mother. These are attempts to benefit a larger class of fetuses.
When attention has been given to the midtrimester fetus, investigations have
often involved the fetus or fetal materials {e.g., amniotic fluid) in the set-
ting of induced abortion.
Investigation of normal human development has generally used observational,
noninvasive methods in the past; much of the work has been anatomic definition.
The expanding interest in the human fetus at present has brought an effort to
gather physiologic, biochemical and pharmacologic data. This has resulted in
increased use of living fetuses close to delivery either at term or at the time
of abortion. Many times these studies are nonbenef icial for the fetal subject
involved and instead seek data to aid future fetuses. With occasional exception,
these studies have not put the fetus at increased risk nor prolonged the delivery
or abortion process. There is often the necessity to complete the experiment
after delivery by obtaining fluid or tissue samples from the placenta, newborn
or abortus. The most active areas of experimentation have been in endocrine
studies of the placenta and fetus and in drug metabolism and disposal.
Animal experimentation has usually preceded human experimentation. In
some areas this has been extensive and in others only exploratory. Many inves-
tigators emphasize the need to establish the appropriateness of an animal model
to the questions being asked and note major differences in the animal and human
pregnancy in some areas. There has been increasing recognition of the need for
primates and increasing use of them in fetal research. A problem has also been
voiced about the huge costs of primate research and the impact on the world
population of these animals should they be extensively utilized.
Fetal tissues are being used more and more in other medical areas including
virology, cancer research and transplantation therapy. The needs of these dis-
ciplines require tissues from recently dead fetuses and haven't strictly involved
research with live fetuses. The definition of death has been an important issue,
however, and fetuses from induced abortions have been extensively used.
There is very little research at present with living, previable fetuses
outside of the uterus. Some metabolic and pharmacologic studies have been done
and a few of these have involved prolonging the life of the fetus. There have
also been a few studies aimed at incubating the fetus outside of the uterus.
Since results have been discouraging and technology seems still to be primitive,
almost no experimentation is currently being done.
Interest in behavioral and psychologic development of the fetus has increased
recently with recognition that sensory perception and other integrated nervous
system function can be studied during fetal life. Experiments have utilized non-
invasive monitoring techniques such as sonography, electrocardiography or electro-
encephalography with either naturally occurring or experimentally applied stimuli.
Data are being developed in normal pregnancies and in pregnancies being studied
for other reasons.
1-26
Until very recently there has been almost no mention of legal or ethical
considerations when reporting fetal research in the medical literature. In the
last few years most reports have stated the legal sanctions for induced abortion
if aborted fetuses have been used and in the past year or two there are often
statements about informed consent. Except in articles discussing ethical issues
there has rarely been any ethical analysis of the experimental procedure.
CURRENT RESEARCH DIRECTIONS ■■ :• . ' ■ "
We attempted to assess current activity in fetal research in two ways.
First, we requested by mail a brief summary of any ongoing or imminent fetal
research projects from each Department of Obstetrics and Department of Pediat-
rics in medical schools in the United States and Canada. Our second approach
was to survey grant applications to the National Institutes of Health for the
period 1971-1974.
Forty replies were received describing fetal research projects currently
in progress or planned. "^ Twelve letters noted that fetal research at their
institution had been halted because of an uncertain legal status at both national
and local levels. In most instances, discontinued research had not been pro-
scribed by federal law (Public Law 93-348) . In addition to the 40 replies that
described research, 26 other letters stated that no research was in progress
and made no comment about any future plans .
In the four year period of NIH grant review, 48 applications were made for
research with live fetuses, 41 were approved by Study Section, and 36 were
funded. 120 There were also 4 contracts involving the living fetus in the years
1973-74. Over 100 additional grant applications dealt with research with the
dead fetus or with fetal tissues.
Current and proposed research with living fetuses mirrored the kinds of
experiments cited in the literature review except there were very few proposals
addressing the previable fetus outside the uterus . Many studies would obtain
amniotic fluid for analysis of various constituents and for use of cells in
tissue culture. Diagnostic questions were being addressed along with attempts
to find greater expression of the fetal genome in the cells. Monitoring studies
involved electrocardiography, ultrasound including transmitter-receivers at the
cervix to follow labor, scalp blood sampling, and use of computers. Studies of
placental transfer of drugs with recovery in aborted fetuses and of drug metab-
olism in fetal tissues were proposed. Tissues for transplantation and for organ
culture were desired.
Fetoscopy, fetal blood sampling, and diagnosis of hemoglobin disorders were
proposed and the effect of fetoscopy on uterine blood flow and contractility
were to be examined. Steroid and other hormone metabolism would be examined in
body fluids of mothers, in placentas, in anencephalic fetuses, and in tissues
of aborted fetuses. Determination of effect on the fetal heart rate of mild
steady state exercise, mild hypoxia, and anxiety in the mother was proposed.
1-27
Malnourished women would receive a food supplement and be contrasted with
a control group as to effects on the fetus. Women with sickle hemoglobinopathies
would be transfused and careful fetal monitoring carried out to try to improve
reproductive performance.
The direction of fetal research continues to want to expand diagnostic
capabilities, define normal metabolic parameters for pregnancy and the fetus
and fetal tissues, and monitor fetuses for problems that can be identified and
treated.
ETHICAL CONSIDERATIONS IN FETAL RESEARCH
1. Introduction. We regard the human fetus as part of the human community
and as such believe that the fetus should legitimately benefit from the main
goals of the medical profession, i.e., the optimizing of human potential for a
full and healthy life, the prevention of disease and deformity, the return of
the diseased human being to a healthy state, and the minimizing of suffering.
The recognition of the legitimacy of the fetus as a patient requires of the
medical profession attempts to learn how to fulfill these goals. This requires
that the human fetus participate in research whose aim is the accomplishment of
those purposes. As with any other class of research subjects, it is paramount
that safeguards be secured which insure that adequate experimental work has been
performed in other systems where applicable, that risks to the research subjects
be acceptably low, that the information sought by the research be deemed signi-
ficant by the biomedical community, and that legal and ethical norms of our
society be central to the design and execution of experimentation.
It is evident that large numbers of fetuses do not enjoy an optimum intra-
uterine life and start extrauterine life with diminished potential. Many fetuses
succumb during intrauterine life or are born diseased and require extensive
therapy which, by that late date, may be ameliorative only. Estimates suggest
that 25 percent of fetuses die in utero and another 2 percent die at the time of
birth or in the first week of life. About 3 percent of all live born infants
have a serious disorder diagnosable at the time of birth apart from problems
of prematurity. Fetal disease and disorders provide a massive medical problem
and one which must be addressed by an ethical profession. Abandonment of the
fetal patient is clearly unethical and abhorent to the profession. Prevention
or correction of disease during fetal or neonatal life, prevention of death at
that period in life, and providing an environment conducive to optimum develop-
ment are benefits for that human individual which extend over the entire life-
time, a potential of seventy or more years. The child and infant for many
decades did not benefit proportionately with adults from advances made in medical
science. Energies and monies expended for the control of medical problems during
1-2J
childhood have historically been much lower than those expended for the problems
of the adult population. The fetus is even more vulnerable in this regard. The
child, the infant, and the fetus are not capable of sounding their own advocacy
and must depend upon other members of the human community. The concept that the
fetus is a therapeutic orphan has substantial validity when one considers the
proportion of the biomedical research effort extended for the fetus and contrasts
that with efforts made at controlling diseases of the adult population. It seems
that the diseases of adulthood and aging continue to receive wide popular support
from a political constituency that views these diseases as more immediate threats
than it views diseases of the fetus. This situation continues even though evi-
dence is accumulating that fetal research, including the understanding of growth
processes and of fetal diseases, may play a key role in solving problems of adult-
onset diseases. But even considering the fetus alone, we believe that progress
in curtailing and preventing diseases of fetal onset should have high priority
and will result in great benefit both to the individuals and to the collective
society. We further believe that fetuses and neonates, as classes of human
beings, have the same right to benefit from medical progress as do other groups
in our community.
2. The Viable Infant. Any viable live-born infant should receive the
best possible medical care including experimental therapies performed under
appropriate safeguards. This is a first responsibility of the medical profes-
sion and of the community. To stay on the safe side of this duty, any possibly
viable live-born subject should be included in this class. At the present time
this might include all subjects over twenty weeks' gestational age or over 500
grams. Viability is primarily a statement about technology, not about the fetus.
Thus a statement about viability is a relative statement and must be reassessed
periodically. We believe that this reassessment should be made at annual or
biannual intervals. In this view, viability cannot be equated with personhood,
but can only be the basis for practical line drawing at a particular moment and
place. The most important reason for drawing such a line as it applies to human
experimentation is the desire to avoid an injury to a fetus that will survive.
To avoid this possibility, a definition of viability should be drawn below the
lower limit of possible viability at a given time. We believe that the viable
infant, even though born very early in gestation, is conceptually no different
than the full-term newborn infant and that considerations of research with
these human subjects requires the same regulations as applied for the protec-
tion of infants and children.
3. The Deceased Fetus. We consider that the fetus which is clearly dead
after delivery should be viewed as any other dead human being. Legal regulations
and ethical constraints on the handling of the deceased human being should be
applicable to the dead fetus. These should permit removal of still living tis-
sues or organs for biomedical research and therapy functions. Examples would
include the carrying out of planned experimentation to learn about fetal metab-
olism, physiology, or disease; beneficial therapy for other human beings like
transplantation of fetal organs, and the teaching of health professionals who
must be the guarantors of continued care and progress in fetal medicine for the
future. For some studies, such as examination of brain ultrastructure and metab-
olism, the transplantation of some tissues, or possibly the recovery of very
fastidious viruses, access to tissues would be required very soon after death.
1-29
This means that the definition of death becomes important and we suggest that
this definition focus on the whole organism. We further believe that the use
of the dead human fetus for any of the above cited purposes must be contingent
upon consent of the person who retains legal responsibility for the deceased
fetus. In almost all circumstances this would be the mother or both parents.
We do not believe that the deceased fetus should be viewed differently if from
a spontaneous abortion rather than an induced abortion and we know of no evidence
to suggest that use of tissues from deceased fetuses increases requests for
abortion .
4. Informed Consent and the Mother. Problems of informed consent are
central to the current societal debate about all kinds of human experimentation
and we do not propose to comment extensively on problems dealing with the con-
senting adult. When a mother is a coparticipant in fetal research, such as
when an abortion is contemplated, her clinical needs must continue to have
primary consideration. Thus the timing and method of abortion should not be
altered in a way that would place the mother at significantly increased risk
for the purpose of experimental design. We do believe however, that the preg-
nant woman, who has received adequate information, should retain the option
and be free to participate in approved research; at times this could include
an alternate method of clinical care.
Considerable controversy exists about the relationship of an investigator
who does fetal research and a mother who may elect or has elected abortion.
It is obvious that investigators cannot be influencing women to decide whether
to have an abortion. After a decision to abort a pregnancy has been made, the
investigator should have a close relationship to the mother if the investigation
will start either before or during the abortion procedure. The mother needs to
know the investigator and she must feel that the investigator will be contin-
ually cognizant of and responsive to her interests. The participation of another
person as intermediary may at times be desirable but at other times unnecessary.
5. Informed Consent and the Fetus. We believe that the human fetus is a
legitimate participant in the human community. The human being is a social
species. A social contract is entered into by the members of the species for
their own protection and for the benefits of collective action to enable a
more satisfactory life for all members of the community. This social contract
has definite limits in our society and does not include the acceptance of undue
risk or any mandate to self sacrifice. It does include a mandate for cooperative
behavior for the benefit of other members of the community and this includes,
most importantly, the preservation of basic human individual rights. It seems
evident in observing adult members of our community that actions are often taken
for the purpose of benefiting other members of the community. Thus we see con-
senting adults freely participating in medical research which has no immediate
benefit to that person. This is done by healthy individuals and also by indi-
viduals who recognize that their death is imminent. The important consideration
in participation by these individuals is that they have the ability to consent
to their own participation. Consent by the fetus is an impossibility. Nonethe-
less we believe that it is reasonable to view the fetal members of the human
community in this regard similarly as adult members. We believe that asking
fetal participation for the purpose of advancing medical benefits for the class
of human fetuses under stated circumstances is acceptable and ethical. These
circumstances are that the information being sought is important to biomedical
advance, that the information cannot be obtained except by the participation of
human fetuses, and that the risks involved are acceptably low. We believe that
a scientific and ethical review process and an advocate for the individual human
fetus should both agree that any proposed research is acceptable. To eliminate
the participation of human fetuses from experimentation because they are unable
to consent, denies fetuses as a class the right to benefit from medical progress
and directly contradicts the presumption that the human fetus is a legitimate
participant in the human community.
In our human community all individuals participate in human experimentation
without their consent at all times. There are planned and unplanned manipula-
tions of the environment including the addition of large numbers of pollutants,
and the application of many types of social and psychologic pressures. Usually,
analysis of the effects of such manipulations is retrospective. Nonetheless, we
recognize how important planned observation and control of many of these param-
eters are to prevent harm to those living today. This is just as true for the
fetus and for the many fetuses yet to be conceived. Planned experimentation and
controlled prospective observation give a much increased likelihood of preventing
harm than the often unplanned way of acting. Again, fetuses as a class should
legitimately benefit from this type of planned experimentation via the mechanism
of proxy consent by an informed advocate .
6. Relationship to Societal Ethics. Research must be guided by the ethical
norms of our society. Over centuries there has been advance in the human's view
of his or her fellows; actions which would be regressive in this regard should
not proceed. Thus activity which would be viewed as dehumanizing or debasing
to our concept of the human individual should be proscribed. We further recog-
nize that in a pluralistic democracy that there must legitimately exist different
views of the human individual and the nature of humanness or personhood. We feel
that no person should participate or have pressures placed upon him or her to
participate in research which violates that person's ethical concepts. We fur-
ther believe that the view of one segment of our population should not dictate
the activities of other large segments of the population as long as fundamental
human rights are preserved. We suggest that any given experimentation should
receive rigorous review for both scientific and ethical content and that this
review be carried out by review boards which are informed about the scientific
and ethical issues and which are representative of the community. We believe
that primary review should occur locally and that there be options for coordina-
tion and analysis of its reviews process at a national level. Scientific and
ethical assessments are equally important. Scientific assessment must consider
experimental design, the nature of the information desired, risk-benefit analysis,
and the use of appropriate alternate means to gain information where applicable.
A review board must be assured that this kind of scientific assessment by appro-
priate competent persons has been carried out. Ethical analysis must be just as
rigorous and must heed the community in which experimentation is being done. We
see a twofold reason for not allowing experimentation which is deemed dehuman-
izing by a large segment of the community. First, activities of this type may,
by a process of slow spread of ideas, undermine the view of the human individual
within the scientific and medical communities. We know of no evidence to suggest
that such a phenomenon occurs but we agree that a reversal of improved or increased
concern for other human beings must be guarded against. Another phenomenon is
more easily documented when experiments are carried out that are unacceptable
to a community. There results a reaction against the scientific and medical
fields such that support of experimentation to enable medical progress is with-
drawn. Thus, in this pragmatic sense, experimentation which is offensive on
ethical grounds has the effect of decreasing all human experimentation, thereby
violating a central ethic of the medical profession to continually seek better
methods of prevention and therapy.
7. The Fetus In Utero. The fetus in utero or in process of being aborted
provides a more difficult ethical analysis than does the dead fetus or the living
viable infant. There is a presumption of viability at any stage in gestation for
the living fetus as long as it remains inside the uterus. Thus experimentation
involving that fetus must have acceptably low risk of any harmful effect on via-
bility or on the potential for meaningful, healthy life. If the process of
abortion has begun, the life of the fetus will soon end. There is debate about
whether different standards apply in that situation and we disagree in our own
analysis. One view holds that no risks can be imposed that would not be accept-
able for the fetus which was continuing life. Another view will accept an
increase in risks if the information is important and alternate ways of obtaining
the information are not practical, if the methods of the experiment are acceptable
in themselves (i.e., would be used in other classes of human subjects), and if the
process of dying for the fetus were not altered in an unacceptable way. In any
event, expected benefits from the experimentation still must be clear and must
require the use of the human fetus to gain the desired information. Ethical con-
siderations as to sensory perception by the fetus also must be addressed. We
know of no evidence to suggest or support a contention that the fetus at mid-
gestation or earlier, when abortions are performed, is aware of pain or has a
psychologic fear of death. We would prefer seeking such information rather than
assuming or ascribing these anthropomorphic parameters of later life to this
early stage of human development when the central nervous system is relatively
primitive. We do not believe that the fetus which will die by elective abortion
or is in the process of dying should be automatically excluded from experimenta-
tion. Imminent death does not automatically exclude participation of children
or adults from medical research. Assessment of an individual research protocol
must still look at the nature of the information sought, the necessity of using
this group of human subjects, and an analysis of whether there was any increase
in suffering entailed by the dying subject. Experimentation in anticipation of
abortion or in process of abortion should not be categorically prohibited but
again should be assessed in terms of risk to the fetus as well as risk to the
mother. With regard to experimentation which starts before abortion starts, we
note that there are many procedures of minimal risk that can be applied to the
intact pregnancy which could yield important information by examination of an
aborted fetus at a somewhat later time. These procedures are noninvasive or
minimally invasive such as the use of sound waves to obtain fetal measurements
for correlation with the abortus or administration of a drug or chemical in trace
amounts, perhaps tagged with a nonradioactive isotope like carbon 13. It would
be important that risk to the fetus were very small, so that if the fetus should
survive to viability, there would be little likelihood that it would have been
harmed. Careful assessment of the individual research protocol should be the
paramount activity rather than categorical prohibition.
8. The Living Previable Fetus. Experimentation with the living previable
subject outside of the uterus falls into two classes. In the first there are
efforts to replace the many functions of the maternal placenta with artificial
alternatives. If this research is meant to be beneficial to a class of fetuses
which cannot survive outside of the uterus at the present time, appropriate work
must have been done in other species, and careful risk analysis should precede
application of the new technologies to the human fetus. The other class of
research with the previable fetus is research which is not beneficial to that ■
particular subject although it would be expected to be beneficial to other
fetuses. In this instance it appears paramount to avoid the possibility of the
fetus surviving with an injury derived from a nonbenef icial experiment. If one
views the fetus as being nonviable as a consequence of the inadequacy of tech-
nology rather than a statement about the lack of personhood in the fetus, then
the previable fetus can be seen as comparable to an adult with a disease or
physiologic derangement which renders that person unable to continue life because
a technological solution to the problem does not exist. The impending death of
the adult would not deprive that person of certain protections as a possible
experimental subject nor would it exclude the individual as a possible subject.
The patient would presumably consent, or an advocate would consent, only to
those procedures which sought important information, unobtainable in any other
way, with minimal risk. These same guidelines should be applied to the pre-
viable fetus outside of the uterus.
9. Parental Rights. In considering, the ethics of fetal research, the
rights and expectations of currently living adults must also be recognized.
Today there is a major concern about restricting the human population of the
world and of conserving natural resources. With attempts to restrict the quan-
tity of human beings born there is a natural wish to maximize the potential
that each human being has at the time of birth. Thus, the quality of each child
is a major and legitimate concern of each individual parent. Parents have his-
torically been given the right of advocacy for their children and this continues
to be the most likely group to best protect the interests of the child, born or
unborn. We believe that parents should be allowed to participate in medical
research for the benefit of their own offspring and of future offspring and to
have their children, both born and unborn, participate when the risks are accept-
ably small and the information sought deemed important. Fetal research has been
of great benefit to many families desiring to have normal children and can be of
continued great benefit in providing normal children to future families. The
government through its tax structure and its involvement in the economy already
excercises considerable pressure upon the reproductive decisions of individuals
in this country. It should even more be the government's role to continue to
support research which will give options for reproductive decisions that have
a better and better likelihood of resulting in normal children.
10. Induced Abortion and Consent. The consent process by which fetuses
participate in research has aroused most controversy when considering research
involving a subject before, during, or after elective abortion. In other cir-
cumstances it would seem that the mother or parents are the most likely to pro-
tect the interests of their fetus. In the setting of elective abortion, the
mother has rejected the possibility of life for her fetus and many persons have
questioned whether she any longer can represent the interests of the fetus . It
is possible, however, that the mother may continue to be the best advocate even
in the setting of elective abortion. It is our experience that the mother con-
tinues to consider the welfare of her fetus during abortion and afterward. At
least it would seem that should she have objection to participation of her fetus
in an experimental protocol, that the fetus would not participate. Another
source of advocacy for the fetus does exist. This is the review process that
assesses the acceptability of the research. When the research is deemed accept-
able for a class of fetuses, then the problem of consent for an individual fetus
must be faced. A variety of procedures for selecting an advocate in addition to
the mother could be proposed.
11. Regulation of Fetal Research. There is concern about the difficulty
of substantive policy achieving an acceptable degree of ethical "rightness" when
it results from a process which is so layered over with political, personal,
religious and other conflicting pressures.
The previous method of protecting the rights of human subjects in this
society has been through procedural safeguards rather than policy on discrete
issues of substance. While such procedural safeguards have had a short history,
and were preceded in this country by a long era of episodes which would now be
considered unethical experimentation, our review of fetal research suggests that
the system has worked well and that the number of ethically questionable studies
is a miniscule part of the whole. Even in those few instances, the projects
have been discontinued in this country.
If this analysis is accurate, there would be considerable advantage to a
policy which required a vigorous review process, coupled with mechanism and
resources for exposure and broad discussion of controversial issues. Such a
policy would be more flexible and adaptable to the rapid changes in this field,
and would reduce the dangers of a policy resulting from political .pressures
rather than reasoned ethical consideration of all relevant data.
For these reasons, it is the recommendation of this study group that the
final policy recommended by the Commission be one which includes an ample
expositipn of the many legal, ethical, and medical issues but which mandates
only a vigorous review process rather than specific restrictions.
CONSEQUENCES OF RESTRICTING RESEARCH
The impact on biomedical advance of restricting fetal research is very
difficult to predict and, by nature, must be speculative. Our literature review
suggests that almost all advances utilizing extrauterine fetal subjects have been
based on research using clearly dead fetuses, or research with therapeutic intent
for the fetal subject. Advances which depended upon intrauterine fetal subjects
in most instances were made with minimally invasive techniques and low risk to
the fetus. Many of these advances could not have been made, however, had there
been a categorical ban in given areas of fetal research. The following suggests
some of the costs that would ensue should fetal research of various types be
banned in the future .
1. Dead Fetus. The deceased fetus after delivery has been and can remain
a very important contributor of living tissues or organs for both research and
therapy. This requires use of a fetus which is only recently dead. Tissue
cultures have been used in the growing of human viruses and the development of
vaccines to protect against these viruses. Restriction of this source of mater-
ial would significantly impede progress in understanding the biology of viral
infection and in developing preventive therapy. Certain human viruses can be
cultured only with the use of human tissues and for some of them only with the
use of human fetal tissues. This may be true of several neuropathic viruses .■'^■'
Another problem in developing vaccines is the presence of animal viruses in the
tissues from nonhuman species. The potential harm of these viruses to human
beings is not known but currently there is significant concern about possible
effects on both investigators and on producers and recipients of viral vaccines
when the vaccine viruses are grown in nonhuman tissues.
Understanding the regulation of growth and its relationship to the neoplas-
tic, cancerous process and to the aging process may depend upon the use of human
fetal tissues in culture. This may especially be true in investigating the
hypothesized link of human viruses with human cancer. Currently there is con-
siderable investigation of the relationship between antigens in placental and
embryonic-fetal tissues and those in neoplastic tissues; this work depends on
tissues from dead fetuses. '^^
A promising avenue of treating individuals who have a genetic defect in one
of their body organs is the transplantation of fetal tissues to that individual.
Fetal tissues often incite less of an immune response and are less likely to
react against the recipient than are child or adult tissues. Fetal thymus, liver,
and bone marrow have been used for this purpose successfully and consideration
has been given to the use of other fetal endocrine glands . Should tissues or
organs not be available from the recently deceased fetus, this avenue of thera-
peutic approach to diseased persons would be unavailable. Animal tissues would
probably be unacceptable because of major immunologic problems.
Tissues and organs from the deceased fetus will be important in defining
the developmental biochemistry and metabolism of the fetus in order to under-
stand disease states. In turn this knowledge will form the basis of projected
therapies aimed at overcoming the effects of genetic disease in the fetus and
of overcoming or preventing the effects of malnutrition on the fetus. For most
purposes where still living fetal tissues from a deceased fetus can be used for
tissue culture, transplantation, or biochemical studies, tissues from an induced
abortion would be more satisfactory than those from a spontaneous abortion.
Tissues from a spontaneous abortion are often of only marginal viability and
planning for the tissues usually cannot be done.
2. Fetus In Utero. In order to diagnose and treat diseases of the fetus
and in order to understand the fetal environment so as to maintain it in an
optimal condition, the human fetus, alive within the uterus, must participate
in the research, at least at the final stages. To categorically deny research
with the living fetus in utero simultaneously denies the fetus the benefit of
research that will allow birth in a healthy condition and denies parents the
possibility of selecting normal intact children rather than diseased children.
With the presumption that the living fetus at any stage during gestation has the
potential for viability, important considerations in deciding about a given
1-35
research protocol are not whether the fetus at a given age is previable or viable
but rather the importance of the information sought, the necessity to seek it in
the proposed manner, and the risk to which the fetus is placed. Research which is
nonbenef icial for the fetus in question may lead to benefits for the large class
of fetuses which can then be defined as either normal or abnormal. This is just
as true during fetal life as it is for children or adults. Description of the
normal situation and the range of normal variability must precede the definition
of abnormal and therefore the ability to diagnose the abnormal state. Likewise
the ability to diagnose the abnormal precedes attempts at preventive or curative
therapy. Thus a ban on nonbenef icial research would preclude knowing how to
define the normal versus the abnormal fetus and further how to prevent or treat
abnormalities. This would close the door to further advances in diagnosing many
more diseases during fetal life that have genetic or environmental origins.
Some of these diseases may not be correctable or treatable in any significant
sense and thus failure to develop ways to diagnose them will negate giving pro-
spective parents an option of having normal rather than diseased offspring. For
other diseases there is already real hope of developing in utero therapies.*^
Major disease problems of the fetus which are a consequence of maternal and
placental abnormalities and which result in malnourished and poorly grown fetuses
or death of the fetus in utero likewise would be more difficult to solve should
nonbenef icial research be proscribed with the fetus in utero.
Understanding development of the fetal nervous system and behavior of the
fetus will require studying the human fetus in utero after initial information
is learned in animals. Swallowing, breathing, response to sound, and response
to touch are known to develop well before full term gestation. Studies in mon-
keys suggest that the fetus is quickly affected, perhaps in a negative way via
asphyxia, 113 when acute anxiety occurs in the mother. To further this knowledge,
which would then serve as the basis of diagnosis and treatment of the fetus and
lead to management of pregnancies in an optimal way for fetal development, will
depend on nonbenef icial research with some fetuses in utero.
Research on fetuses whose lives are about to be ended by elective abortion
involves a special class of potential research subjects. In these subjects it
is possible to carry out research procedures that will give information about
the fetus at that stage of gestation which is largely unavailable if the fetus
continues in utero. The current development of instrumentation to view the
fetus and sample the fetal blood stream or otherwise obtain a tiny sample of
fetal tissue has made use of fetal subjects about to be aborted or in the process
of abortion. After animal experimentation had indicated the feasibility of such
approaches but not at all the possible problems to be anticipated in the human
situation, it was necessary to utilize human pregnancies to test out the ideas
and the instrumentation. The techniques give major hopes of diagnosing a wide
range of fetal disease, of monitoring the progress or adequacy of treating a
diseased fetus, and of defining normal and abnormal while the fetus is living,
before death occurs in the process of abortion. Although this technique is
now entering the stage of clinical trial, its further development and develop-
ment of similar technologies can be done most safely if fetuses who are being
aborted are the first to participate in the new research. A ban on this kind
of research forces the development of new technology in fetuses where the intent
is to maintain viability and carry the fetus to the end of gestation. Should
there be unrecognized or unknown risks associated with the procedure, they will
be discovered from this group of fetuses rather than from a group of fetuses who
will not live to grow into children and adults.
Placing a ban on research which started before an abortion process started
would also prohibit the gaining of significant information about the fetus in its
normal environment. Techniques which are noninvasive or which are invasive with
very low, if any, risk exist at the present time and are being developed further.
These include amniocentesis, the use of sound waves, the use of nonradioactive
isotopes such as carbon 13 or tracer amounts of radioactive isotopes, and the
monitoring of fetal movements or electrical activity from outside of the uterus.
Such techniques could be used in anticipation of abortion without any significant
risk to the fetus. If abortion were never carried out, the fetus would not have
suffered any problem and the only loss would be the research data. The important
consideration in this type of research is the risk to which the fetus is to be
placed by the research being planned.
The field of fetal pharmacology is one of the most crucial areas requiring
research with the living fetus in utero and with the fetus that will be or is
being aborted. Recent reviews in the United Kingdom and the United States docu-
ment that during pregnancy women take, on average, six pharmacologic agents. ^°
In addition, dietary manipulations are often carried out during pregnancy. The
effects of this enormous amount of drug therapy, some physician-prescribed and
some self-prescribed, on a developing fetus are almost entirely unknown. In a
very real sense the human fetus is incubated in a sea of drugs. We know very
little about the effect of these drugs on the human fetus or the distribution
within the human fetus. Drugs may distribute differently in lean (e.g., mal-
nourished) fetuses than in obese (e.g., diabetic) fetuses due to the respective
lipid solubilities of each drug. Drugs may concentrate in different tissues
depending upon the time and gestation at which studies are carried out and upon
the nature of the fetal circulation at that point in gestation. Consequently,
different pharmacodynamic effects may be manifest at discrete points in gestation
making it essential to study tissues obtained over a broad time spectrum. Unan-
ticipated accumulation of drugs within its environment may have significant
teratogenic effects on a given fetal organ. Thus, for intelligent information
about drug effects in the fetus, one requires detailed information about the
pharmacokinetics of drug transfer across the placenta and into various parts of
the fetus, and one requires detailed information on the disposition of the drug
both anatomically and metabolically within the fetus. The use of fetoscopy to
obtain a small blood sample immediately before abortion would enable investiga-
tors to study the transfer of the drug from the maternal circulation to the fetal
circulation. The use of aborted fetuses would enable the determination of where
drugs go within the fetus and what happens to them in different parts of the
fetus. When in utero treatment of a fetus is being tried, sampling of amniotic
fluid or fetal tissue may be necessary to know if the therapy is of any use. At
term, the study of the transfer of pharmacologic agents to the fetus and the con-
centration of drugs reached in the fetal circulation can be done by giving agents
just before the induction of labor or during labor and then measuring concentra-
tions of drugs in the newborn infant. Continued development of fetal monitoring
to make labor as safe as possible for the fetus will also require investigation
of the fetus at this final stage of pregnancy.
1-37
Important areas of obstetric research with primary relationship to the mother
also require involvement of the fetus in the research. An active area of research
has been the development of effective analgesics and anesthetics to be used during
labor which are also safe for the fetus and neonate.'^ Studies related to improv-
ing methods of inducing abortion, such as the development of new chemical compounds
to enhance the safety of abortion, would be inhibited if there was a ban on researcl
which involved the living fetus in utero. Research seeking ways of inhibiting pre-
mature labor simultaneously involves the living fetus. This research is necessary
if obstetricians are to enable the fetus to remain inside the uterus, where it can
most safely grow, rather than being born prematurely to the many dangers of extra-
uterine life.
For many of the studies mentioned above, the aborted fetus from a spontan-
eous abortion does not provide an adequate research model. For some purposes,
e.g., a drug transfer study, the research must start at some interval before
abortion starts. The abortion process itself is very unpredictable; the time at
which the fetus dies is not known and in a spontaneous abortion may have predated
the onset of the abortion by days or even weeks. Ofttimes the fetus after spon-
taneous abortion, because of a long period of in utero death, provides limited
information about biochemical or metabolic activity or the distribution of chem-
icals within various fetal tissues.
3. The Previable Fetus Outside the Uterus. One major area of research with
the extrauterine previable fetus in the future will probably be aimed at supporting
life of the fetus in ways significantly different than those used today until the
fetus is large enough to be sustained in a more conventional premature nursery.
These research attempts will be toward the development of placental functions
whereby gas exchange and delivery of nutrients are carried out artificially out-
side of the uterus. Extensive development and success in other animal species
would necessarily precede attempts in the human. Initial human studies will
likely be done in seriously ill viable premature infants. At some stage, if
these advances are to be made, there will be application of the methods to what,
at the time, would be termed a previable fetus. A ban on this type of research
might preclude the opportunity of life for this group of human patients in the
future .
A second major class of experimentation with the previable fetus outside
the uterus is research which would establish metabolic, physiologic, or psycho-
logic parameters at that stage of human life. For example, the study of brain
electrical activity at a certain fetal age could be carried out outside of the
uterus, or a study of sense organ maturity with the purpose of knowing whether
light or sound energy had the potential of harming a sense organ at the same
stage in utero might be learned from the extrauterine fetus before death. The
safety of new diagnostic or therapeutic techniques that are to be applied to the
fetus in utero in some instances could be answered in part by investigations in
the previable fetus outside of the uterus. These studies would not be beneficial
to the given fetal subject, but could be to many other fetuses.
There would seem to be little difference in the information obtainable from
a previable fetus which was the product of a spontaneous abortion versus the
fetus that was a product of an induced abortion if the investigator was adequately
prepared when either type of fetus became available. In practice, the planned
nature of induced abortion would make the intelligent gathering of information
much more possible.
The requirement of using the human fetus in gathering knowledge applicable
to the human fetal situation varies considerably depending upon the questions
being asked. Certain animal models are very satisfactory for developing some
types of intrauterine monitoring and intrauterine instrumentation. For other
problems the human pregnancy is the only practical model and always becomes so
when one wishes to transfer information obtained in animal species to the human
situation. Thus learning whether it was possible to draw blood from the fetal
blood stream progressed from the theoretical as assessed in animal species to
the practical when attempted in the human pregnancy just before abortion. In
some areas of metabolism and physiologic function, there are quite satisfactory
animal models. In other areas the schedule of biochemical and physiologic matu-
ration is entirely different in the human species and only the human species can
be used to acquire the desired knowledge. The same thing is true for the trans-
fer of drugs from the mother to the fetus and for the disposition and metabolism
of those drugs within fetal tissues. Each research question must be addressed
individually in this regard to know whether appropriate animal research could be
done in seeking to answer a problem of human fetal medicine. This reinforces
the conclusion of this study group that categorical bans on areas of research
are short-sighted and that instead a process of rigorous review of individual
research projects is much to be preferred.
1-39
REFERENCES
1. World Health Organization, "Maturation of Fetal Body Systems," Technical
Report Service 540, 1974.
2. Arey, L.B., Developmental Anatomy: A Textbook and Laboratory Manual of
Embryology, 7th ed., Philadelphia: W.B. Saunders Co., 1965.
3. Brent, Robert L. and Jensh, R.P., "Intra-uterine Growth Retardation,"
Advances in Teratology 2:140-228, 1967.
4. Moore, Keith L. , The Developing Human, Philadelphia: W.B. Saunders Co.,
1973.
5. Raid, D.E., Ryan, K. J. , and Benirschke , K. , Principles and Management of
Human Reproduction, Philadelphia: W.B. Saunders Co., 1972.
6. Smith, D.W. , Recognizable Patterns of Human Malformation : Genetic, Embry-
ologic and Clinical Aspects, Philadelphia: W.B. Saunders Co., 1970,
pp. 347-349.
7. Warkany, J., Congenital Malformations: Notes and Comments, Chicago: Year
Book Medical Publishers, Inc., 1971.
8. Gruner, J.E., "The Maturation of Human Cerebral Cortex in Electron Microscopy
Study of Post-Mortem Punctures in Premature Infants," Biology of the Neonate
16:243, 1970.
9. Murphy, B.E.P.; Clark, S.J.; Donald, I.R., et al., American Journal of
Obstetrics and Gynecology 118:538, 1974.
10. Simmer, H.H.; Tulchinsky, D. ; Gold, E.M., et al., "On the Regulation of
Estrogen Production by Cortisol and ACTH in Human Pregnancy at Term,"
American Journal of Obstetrics and Gynecology 119:283, 1974.
11. "Blood Glucose of the Human Fetus Prior to and During Labor," Acta Paediatrica
Scandinavica 57:512, 1958.
12. Morris, J. A.; Hustead, R.F.; Robinson, R.G., et al., "Measurement of Feto-
placental Blood Volume in the Human Previable Fetus," American Journal
of Obstetrics and Gynecology 118:927, 1974.
13. Queenan, J.T.; Thompson, W.; Whitfield, C.R.; and Shah, S.I., Amniotic Fluid
Volumes in Normal Pregnancies.
REFERENCES (Continued)
14. Hauschka, S.D., "Clonal Analysis of Vertebrate Myogenesis," Developmental
Biology 37:329, 345, 1974.
15. Andersson, K.E., Gennser, G. , and Nilsson, E., "Con*-.ractility of Isolated
Human Foetal Hearts," Acta Physiologica Scandinavica 80 (Suppl. 353:5,
1970.
15. Rsch, B.A.; Papp, J.G.; Szontagh, F.E., et al . , "Comparison of Spontaneous
Contraction Rates of In Situ and Isolated Fetal Hearts in Early Pregnancy,"
American Journal of Obstetrics and Gynecology 118:73, 1974.
17. Daves, G.S., "Breathing Before Birth in Animals and Man. An Essay in Devel-
opmental Medicine," New England Journal of Medicine 290:557, 1974.
18. Duenhoelter, J.H. and Pritchard, J.A. , "Human Fetal Respiration II. The Fat
of Intraamniotic Hypaque and ^■'■Cr Labeled Red Cells," Obstetrics and
Gynecology 43:878, 1974.
19. Goodlin, R.C. and Schmidt, W. , "Human Fetal Aroused Levels as Indicated by
Heart Rate Recordings," American Journal of Obstetrics and Gynecology
114:613, 1972.
20. Sakabe, N., Arayame, T. , and Suzuki, T. , "Human Fetal Evoked Response to
Acoustic Stimulation," Acta Otolaryngologica , Suppl 252:29, 1969.
21. Walker, D., Grimwade, J., and Wood, C. , "Intrauterine Noise: A Component
of the Fetal Environment," American Journal of Obstetrics and Gynecology
109:91, 1971.
22. Sadovsky, E. , Mahler, Y. , and Polishuk, W.Z., "Correlation Between Electro-
magnetic Recording and Maternal Assessment of Fetal Movement," Lancet
1:1141, 1973.
23. Mistetta, CM. and Bradley, R.M. , "Taste and Swallowing In Utero," British
Medical Bulletin 31:80, 1975.
24. Smith, C.N., "Exploratory Methods for Testing the Integrity of the Fetus
and Neonate," Journal of Obstetrics and Gynaecology of the British Common-
wealth 72:920, 1965.
25. Humphrey, T. , "The Development of Human Fetal Activity and Its Relation to
Postnatal Behavior," Advances in Childhood Developmental Behavior 5:1, 1970.
26. Burt, R.L. and Davidson, I.W.F., "Insulin Half-Life and Utilization in Normal
Pregnancy," Obstetrics and Gynecology 43:151, 1974.
27. Gant, N.F. ; Chand , S . ; Whalley, P. J.; and Macdonald, P.C, "The Nature of
Pressor Responsiveness to Angiotension II in Human Pregnancy," Obstetrics
and Gynecology 43:854, 1974.
REFERENCES (Continued)
28. Stein, Z. and Susser, M. , "The Dutch Famine. 1944-1945, and the Reproductive
Process," Pediatric Research 9:70,76, 1975.
29. Lechtig, A.; Habicht, J.; Yarbrough, C; Delgado, H.; Guzman, G.; and
Klein, R.E., "Influence of Food Supplementation During Pregnancy on
Birth-Weight in Rural Populations of Guatemala," Nutrition Congress
Vol. 2, New York: Karger, Basel, 1974.
30. Kim, Y.J. and Felig, P., "Maternal and Amniotic Fluid Substrate Levels
During Caloric Deprivation in Human Pregnancy," Metabolism 21:507, 1972.
31. Milunsky, A., The Prenatal Diagnosis of Hereditary Disorders, Springfield,
Illinois: C. Thomas, 1973.
32. Burton, B.K., Gerby , A.B., and Nadler, H.L., "Present Status of Intrauterine
Diagnosis of Genetic Defects," American Journal of Obstetrics and Gynecology
118:718, 1974.
33. Valenti, C, "Perinatal Genetic Studies and Counseling," Clinical Perinatalogy
S. Aladjem (ed.), St. Louis: Mosby Co., 1974.
34. Kaback, M.M. , Leisti, J.T., and Levine, M.D., "Prenatal Genetic Diagnosis,"
Endocrine and Genetic Diseases of Childhood, L. Gardner (ed.), W.B. Saunders
Pub., 2nd Edition, 1975, in press.
35. Russel, J.B.B., "Radiology in the Diagnosis of Fetal Abnormalities," Journal
of Obstetrics and Gynaecology of the British Commonwealth 76:345, 1969.
36. Noonan, CD., "Antenatal Diagnosis of Achondroplasia with Comment on Deuel's
•Halo" Sign," American Journal of Obstetrics and Gynecology 101:929, 1968.
37. Queenan, J.T. and Gadow, E.C. , "Amniography for Detection of Congenital Mal-
formations," Obstetrics and Gynecology 35:648, 1970.
38. Aguero, 0. and Zieghelboim, I., "Fetography and Molegraphy," Surgery, Gyne-
cology and Obstetrics 130:649, 1970.
39. Wiensenhann, P.F., "Fetography," American Journal of Obstetrics and Gynecology
11:819, 1972.
40. Jeffcoate, T.N. A.; Fliegner, J.R.H.; Russell, S.H.; Davis, J.C.; and Wade, A.D.
"Diagnosis of the Adrenogenital Syndrome Before Birth," Lancet 2:553, 1965.
41. Frasier, S.D., Weiss, B.A. , and Horton, R. , "Amniotic Fluid Testosterone:
Implications for the Prenatal Diagnosis of Congenital Adrenal Hyperplasia,"
Journal of Pediatrics 84:738, 1974.
42. Ampola, M.G.; Mahoney, M.J.; Nakamura, E.; and Tanaka, K., "In Utero Treatment
of Methylmalonic Acidemia with Vitamin B^^'" Pediatric Research 8:387, 1974.
1-42
REFERENCES (Continued)
43. Stein, Z., Susser, M. , and Guterman, A., "Screening Programmed for Preven-
tion of Down's Syndrome," Lancet 1:305, 1973.
44. Kaback , M.M. and O'Brien, J.S., "Tay-Sachs : Prototype for Prevention of
Genetic Disease," Medical Genetics, V.A. McKusick and R. Claiborne (eds.)
H.P. Publ., 1973.
45. Harris, M. (ed.), "Early Diagnosis of Human Genetic Defects: Scientific
and Ethical Considerations," Fogarty International Center Proceedings
No. 6, Washington, D.C.: U.S. Government Printing Office, 1971.
46. Hilton, B. ; Callahan, D.; Harris, M. ; Condliffe, P.; and Berkley, B. (eds.),
"Ethical Issues in Human Genetics," Fogarty International Center Proceedings
No. 13, New York: Plenum Press, 1973.
47. Fletcher, J., "Ethical Aspects of Genetic Controls," New England Journal of
Medicine 285:776, 1971.
48. Liley, A.W., "The Use of Amniocentesis and Fetal Transfusion in Erythroblas-
tosis Fetalis," Pediatrics 35:836, 1965.
49. Queenan , J.T., "Amniocentesis and Transamniotic Fetal Transfusion for Rh
Disease," Clinical Obstetrics and Gynecology 9:491, 1966.
50. Charles, A.G. and Friedman, E.A. (eds.), Rh Isoimmunization and Erythro-
blastosis Fetalis, New York: Appleton, 1969.
51. Adamsons, K. , Jr., "Fetal Surgery, Current Concepts," New England Journal
of Medicine 275:204, 1966.
52. Brock, D.J.H. and Sutcliffe, R.G., "Alpha-Fetoprotein in the Antenatal
Diagnosis of Anencephaly and Spina Bifida," Lancet 2:197, 1972.
53. Brock, D.J.H. , Bolton, A.E., and Monaghan , J.M., "Prenatal Diagnosis of
Anencephaly Through Material Serum-Alphafetoprotein Measurement," Lancet
2:7835, 1973.
54. Harris, R. ; Jennison, R.F.; Barson, A. J.; Laurence, K.M. ; Ruoslahti, E.;
and Seppala, M. , "Comparison of amniotic Fluid and Maternal Serum Alpha-
Fetoprotein Levels in the Early Antenatal Diagnosis of Spina Bifida and
Anencephaly," Lancet 429, 1974.
55. Roux, J.F. and Nakamura, J., "Determination of Fetal Maturation by Amnio-
centesis," Clinical Perinatology, S. Aladjem (ed.), St. Louis: Mosby S
Co., 1974.
56. Gluck, L. and Kulovich, M. , "Lecithin Sphingomyelin Ratios in Amniotic Fluid
in Normal and Abnormal Pregnancy," American Journal of Obstetrics and Gyne-
cology 115:539, 1973.
1-43
REFERENCES (Continued)
57. Roux, J.F., et al., "Further Observations on the Determination of Gestational
Age by Amniotic Fluid Analysis," American Journal of Obstetrics and Gyne-
cology 116:633, 1973.
58. Dawes, G.S., "Fetal Respiratory Movements Rediscovered," Pediatrics 51:965,
1973.
59. Dawes, G.S., "The Clinical Significance of Fetal Breathing Movements,"
Proceedings of the International Symposium on Perinatal Medicine,
Finnish Medical Society, Helsinki, 1975.
50. Liggins, G.C. and Howie, R.N., "A Controlled Trial of Antepart\am Gluco-
corticoid Treatment for Prevention of RDS in Premature Infants," Pediatrics
50:515, 1972.
51. De La Rama, F.E., Jr. and Merkatz, I.R., "Evaluation of Fetal Scalp pH with
a Proposed New Clinical Assessment of the Neonate," American Journal of
Obstetrics and Gynecology 107:93-99, 1970.
62. Hobel, C.J., Hyvarinen, M.A. , and Oh, W. , "Abnormal Fetal Heart Rate Patterns
and Fetal Acid-Base Balance in Low Birth Weight Infants in Relation to
Respiratory Distress Syndrome," Obstetrics and Gynecology 39:83-88, 1972.
53. Yoshioka, T. and Roux, J.F., "Correlation of Fetal Scalp pH, Glucose, Lactate
and Pyruvate Concentrations with Cord Blood Determinations at Time of
Delivery and Cesarean Section," Journal of Reproductive Medicine 5:209-214,
1970.
54. Carretti, N., "Analisi Interpretativa Di Alcuni Quadri Elettroencefalograf ici
Fetali in Travaglio Di Parto," Riv. Obstet . Ginecol . 105:39-51, 1970.
65. Mann, L.I., Prichard, J.W. , and Symmes , D. , "EEG, ECG, and Acid-Base Obser-
vations During Acute Fetal Hypoxia," American Journal of Obstetrics and
Gynecology 105:39-51, 1970.
55. Bentrem, G.C, Perkins, P., and Waxman, B. , "Newer Methods of Evaluating
Fetal Maturity," American Journal of Obstetrics and Gynecology 106:917-919,
1970.
57. Roux, J.F., Nakamura, J., and Brown, E.G., "Further Observations on the
Determination of Gestational Age by Amniotic Fluid Analysis," American
Journal of Obstetrics and Gynecology 116:633, 1973.
68. Creasman, W.T. , Lawrence, R.A. , and Thiede , H.A., "Fetal Complications of
Amniocentesis," Journal of the American Medical Association 204:949, 1958.
69. Liley, A.W. , "The Technique and Complications of Amniocentesis," Afetv' Zealand
Medical Journal 59:581, 1950.
1-44
REFERENCES (Continued)
70. Cook, L.N., Shott, R.J., and Andrews, B.F., "Fetal Complications of Diagnos-
tic Amniocentesis," Pediatrics 53:421, 1974.
71. Garrett, W.J. and Robinson, D.E., "Assessment of Fetal Size and Growth Rate
by Ultrasonic Echoscopy," Obstetrics and Gynecology 38:525, 1971.
72. Garrett, W. J. , Phil, D. , and Robinson, D.E., "Fetal Heart Size Measured In
Vivo by Ultrasound," Pediatrics 46:25, 1970.
73. Donald, I., "New Problems in Sonar Diagnosis in Obstetrics and Gynecology,"
American Journal of Obstetrics and Gynecology 118:299, 1974.
74. Brent, R.L. and Gorson, R.O. , "Radiation Exposure in Pregnancy," Current
Problems in Radiology, Vol. 11, No. 5, Sept. - Oct., 1972.
75. Walknowska, J., Conte , F.A., and Grumbach, M.M., "Practical and Theoretical
Implications of Fetal/Maternal Lymphocyte Transfer," Lancet 1:1119, 1969.
76. Morrow, G., Ill, Schwarz , R.H., and Hallock, J. A., "Prenatal Detection of
Methylmalonic Acidemia," Journal of Pediatrics 77:120, 1970.
77. Hobbins, J.C. and Mahoney, M.J., "In Utero Diagnosis of Hemoglobinopathies.
Technic for Obtaining Fetal Blood," New England Journal of Medicine
290:1065, 1974.
78. Benzie, R.J, and Doran, T.A., "The 'Fetoscope' - A New Clinical Tool for
Prenatal Genetic Diagnosis," American Journal of Obstetrics and Gynecology
121:460, 1975.
79. Schenkel, B. , et al . , "Non-Prescription Drugs During Pregnancy: Potential
Teratogenic and Toxic Effects Upon Embryo and Fetus , " Journal of Reproduc-
tive Medicine 12:27, 1974.
80. Forfar, J., et al., "Epidemiology of Drugs Taken by Pregnant Women: Drugs
That May Affect the Fetus Adversely," Clinical Pharmacology and Therapeu-
tics 14:832, 1973.
81. Glass, L. , et al . , "Exposure to Quinine and Jaundice in a G-6-P-D Deficient
Newborn Infant," Journal of Pediatrics 82:735, 1973.
82. Ganguin, G. , et al., "Streptomycin Therapy During Pregnancy and Its Effect
On the Hearing of the Offspring," Z. Laryngology, Rhlnology and Otology
49:496, 1970.
83. Kauffman, R.E. , Morris, J. A., and Azarnoff, D.L., "Placental Transfer and
Fetal Urinary Excretion of Gentamycin During Constant Rate Maternal
Infusion, Pediatric Research 9:104, 1975.
1-45
REFERENCES (Continued)
84. Hirsch, H. , "Treatment vith Antibiotics During Pregnancy," Munch. Med.
Wochenschr. 111:32, 1969.
85. Sutherland, J., "Fetal Cardiovascular Collapse of Infants Receiving Large
Amounts of Chloramphenicol," American Journal of Diseases of Children
97:761, 1959.
86. Selenkow, H., "Antithyroid-Thyroid Therapy of Thyrotoxicosis During Preg-
nancy," Obstetrics and Gynecology 40:117, 1972.
87. Hamburger, J., "Management of the Pregnant Hyperthyroid. The Argument
Against Combined Anti-Thyroid-Thyroid Therapy," Obstetrics and Gynecology
40:114, 1972.
88. Carrington, E., "Editorial: Relationship of Stilbesterol Exposure In Utero
to Vaginal Lesions in Adolescence," Journal of Pediatrics 85:295, 1974.
89. Poland, B. , et al., "The Influence of Recent Use of an Oral Contraceptive
on Early Intrauterine Development," American Journal of Obstetrics and
Gynecology 116:1138, 1973.
90. Nora, J.J., et al., "Can the Pill Cause Birth Defects?" New England Journal
of Medicine 291:731, 1974.
91. Bobrowitz, H., "Ethambutol in Pregnancy," Chest 86:20, 1974.
92. Pawliger, D.F., et al., "Normal Fetus After Cytosine Arabinoside Therapy,"
Annals of Internal Medicine 74:1012, 1971.
93. Gravina, E., "Serum Complement in the Infants of Mothers Treated with Immuno-
depressive Agents," Attual Ostet Ginecol 1:222, 1968.
94. Margolin, F., et al., "Hemorrhagic Disease of the Newborn. An Unusual Case
Related to Maternal Ingestion of An Antiepileptic Drug," Pediatric Clinics
of North America 11:59, 1972.
95. Hill, R. , et al., "Infants Exposed In Utero To Antiepileptic Drugs," American
Journal of Diseases of Children 127:645, 1974.
96. Mirkin, B., "Diphenylhydantoin: Placental Transfer, Fetal Localization,
Neonatal Metabolism and Possible Teratogenic Effects," Journal of Pediatrics
78:329, 1971.
97. Glass, L. , et al . , "Effect of Heroin on Corticosteroid Production in Pregnant
Addicts and Their Fetuses," American Journal of Obstetrics and Gynecology
117:476, 1973.
98. Idanpaan-Heikkila, J., et al., "Elimination and Metabolic Effects of Ethanol
in Mothers, Fetus and Newborn Infant," American Journal of Obstetrics and
Gynecology 112:387, 1972.
1-46
REFERENCES (Continued)
99. Freeman, R.K., et al., "Fetal Cardiac Response to Paracervical Block Anes-
thesia," American Journal of Obstetrics and Gynecology 113:583, 1972.
100. Teramo, K. , "Fetal Bradycardia After Paracervical Block," American Journal
of Obstetrics and Gynecology 115:872, 1973.
101. Bolognese, R. J. , Corson, S.L., Seven, J.L., et al., "Rubella Vaccination
During Pregnancy," American Journal of Obstetrics and Gynecology 112:902,
1972.
102. Yamauchi, T., Wilson, C, and St. Geme , J.W. , "Transmission of Live, Attenu-
ated Mumps Virus to the Human Placenta," New England Journal of Medicine
290:710, 1974.
103. Wentz, A.C., Burnett, L.S., and King, T.M., "Methodology in Premature Preg-
nancy Termination," Part I, Surgery, Gynecology and Obstetrics 28:2-19,
1973; Part II, Surgery, Gynecology and Obstetrics 29:6-42, 1974.
104. Adam, P.A.J. ; Raiha, N.; Rahiala, E.L., et al . , "Cerebral Oxidation of
Glucose and D-BOH-Butyrate by the Isolated Perfused Fetal Head," Pediatric
Research 7:309, 1973.
105. King, K. ; Schwartz, R. ; Sasrikoski, S.; Adam, P.A.J. , et al., "Differing
Sensitivity of Human Fetal Receptor Sites to Arginine-Induced Insulin and
Growth Hormone Release," Pediatric Research 7:329, 1973 (abstract).
105. Taylor, T. , Coutts, J.R.T., and Macnaughton, M.C., "Oestrogen Formation in
Human Foetuses Perfused with (4--'-^C) Progesterone," Acta Endocrinologica
75:759, 1974.
107. Mestyan, J., Fekete, M. , Jarai, I., et al., "The Postnatal Changes in the
Circulating Free Amino Acid Pool in the Newborn Infant," Biology of the
Neonate 14:164, 1969.
108. Cassady, G. , "Bromide Space Studies in Infants of Low Birth Weight,""
Pediatric Research 4:14, 1970.
109. Gupta, H.L., Singh, H. , Dhatt, P.S., et al . , "Relationship of Cord Blood
Foetal Hemoglobin to Birth Weight and Length of Gestation," Indian Journal
of Medical Research 61:903, 1973.
110. Goodlin, R.C., "Cutaneous Respiration in a Fetal Incubator," American
Journal of Obstetrics and Gynecology 86:571, 1963.
111. Westin, B., Nyberg, R. , and Enhornung, G., "A Technique for Perfusion of the
Previable Human Fetus," Acta Paediatrica Scandinavica 47:339, 1958.
1-47
REFERENCES (Continued)
112. Chamberlain, G. , "An Artificial Placenta: The Development of an Extracor-
poreal System for Maintenance of Immature Infants with Respiratory Prob-
lems," American Journal of Obstetrics and Gynecology 100:615, 1958.
113. Morris, J. A., Haswell, G.L., Hustead, R.F., "Research in the Human Midtri-
mester Fetus," Obstetrics and Gynecology 39:634, 1972.
114. Sasrikowski, S. and Castren, 0., "Distribution and Metabolism of H-^ - Nora-
drenaline in Various Tissues of the Human Fetus in the Fetoplacental Unit,"
Acta Obstetricia et . Gynecologica Scandinavica (Supp 9) 50:60, 1971.
115. Ermine, M. ; Benegiano, G. ; de la Torre, B.; and Diczfalusy, E. , "Studies
on the Metabolism of C-19 Steroids in the Fetoplacental Unit," Acta
Endocrinologica 72:786, 1973.
116. Lerner, U. , Saxena, B.N., Diczfalusy, E. , "Extracorporeal Perfusion of the
Human Fetus, Placenta and Fetoplacental Unit," Acta Endocrinologica
72:786, 1973.
117. Turner, R.C., Schneeloch, B.C., Paterson, P., "Changes in Plasma Growth
Hormone and Insulin of the Human Fetus Following Hysterotomy," ^cta
Endocrinologica 66:577, 1971.
118. Taylor, T. , Coutts , J.R.T., MacNaughton, M.D., "Human Fetal Synthesis of
Testosterone from Perfused Progesterone," J. of Endocrinology 60:321, 1974.
119. Copies of these letters are on file with the Commission staff.
120. Short descriptions of the applications are on file with the Commission staff.
1-48
FETAL RESEARCH
AND THE VALUE OF LIFE
Sissela Bok, Ph.D.
SISSELA BOK, Ph.D.
Dr. Bok is presently a lecturer in Medical Ethics, both
at Radcliffe Institute and in the Harvard-MIT
Program on Health and Technology.
PD 304112-5
Fetal Research
and the Value of Life
I . INTRODUCTION - ■ ■
As our ability to predict the effects of social policies on human lives
increases, the dilemmas of weighing these effects humanely and justly grow more
intense. Fetal research throws these dilemmas into sharp relief, since it raises
hopes for the alleviation of much suffering but also fears of abuses and brutali-
zation.i.6.7,8,?6.27 , , . -
Fetal research affects human lives in three controversial ways:
1. The processes of fetal research can use some fetuses - aborted
or about to be aborted - for the benefit of others.
2. The results of diagnostic fetal research can at times influence
parental choices for and against abortion. _ ^ ..:
3. The results of fetal research could save hundreds of thousands
of babies from early death or severe disease.
All these effects on lives must be seen, in turn, against the background
of environmental, social, and individual factors which already harm the fetus.
Environmental radiation, working conditions, or maternal taking of drugs, for
example, affect fetuses, yet the nature and incidence of these effects are not
yet thoroughly known.
At present there is profound disagreement as to how these different harms
and benefits should be weighed. Ethical views play a major role in this dis-
agreement, and must be analyzed in order to set national policy for fetal ■'
research.
The intense opposition to much fetal research stems from two lines of argu-
ment, both connected with positions on abortion.
The first argument holds that a fetus is a person, and should have the same
rights with respect to experimentation as any other person. Research without
consent by or benefit for the fetuses subjected to the research, therefore, is
seen as an assault upon their humanity.
The second argument is designed to speak to those who do not share the
premise of early fetal personhood. It stresses, not the inherent wrong in fetal
research, but rather the fearful consequences flowing from a social policy per-
mitting such research. It holds that fetal research risks the development of
attitudes in researchers, hospital personnel, and society in general which are
insufficiently sensitive to human rights and interests. In this way, if we
allow fetal research to continue, there will be no way of stopping at research
early in fetal life; eventually, society may come to permit practices of using
infants, children, those condemned to die, and all who are defenseless. (Already,
according to this argument, in utero research, in anticipation of abortion, con-
stitutes a threat to fetuses who might have lived unharmed, had their mothers
been permitted to change their minds about their abortions. This last concern,
though important, can be met by well drawn and practicable regulations, which
I shall suggest on pages 2-7 to 2-10 of this paper.)
These two main objections might appear to threaten all fetal research not
therapeutic for the subjects themselves; they will be the principal subjects of
this paper. I hope to show that the first argument is inapplicable to fetal
research, and that safeguards can be provided so that the second argument fails
to apply to such research. Most importantly, this paper is intended to stress
the fact that the safeguards we consider for fetal research should be extended
to those numerous experiments and therapeutic ventures on pregnant mothers not
now considered fetal research but placing fetuses at risk.
II. DEFINITIONS
1. The Living Fetus — the living product of conception — will be discussed in
this paper as follows :
a. In utero from the time of ascertainable presence up to the
beginning of abortion or labor.*
b. During process of abortion or labor.
c. After abortion but prior to viability.
Experiments using solely dead fetuses or fetal materials will not be con-
sidered here; presumably regulations governing autopsy will be applicable in
such cases. Nor will experiments on clearly viable fetuses after birth be con-
sidered here; such experiments should be regulated no differently than all others
where infants and young children are at risk.
2. Experimentation. All intervention in a study which can have an effect on
the fetus will be considered here, whether it be intervention involving the
maternal-fetal unit, the fetus alone, or the mother alone, so long as she is
pregnant.
*To preserve simplicity, "fetus" will stand for both "fetus" and "embryo" and
any other appropriate terms.
3. Viability of the Fetus. In the present study, the following definition will
be used, suggested in the August 23, 1974, DHEW Proposed Policy t^^
The ability of the fetus, after either spontaneous or induced
delivery, to survive (given the benefit of available medical
therapy) to the point of independently maintaining heartbeat
and respiration.
The purpose of the present article, however, is to avoid having to draw a
line at viability because of the difficulties of ascertaining viability and the
chances of error. 2 Rather, I shall suggest a time earlier in fetal development
beyond which experiments should at present be ruled out — a time when viability
is not yet in question.
DIMENSIONS
In order to arrive at useful distinctions among the different kinds of
research, the chart entitled Dimensions of Fetal Research on the following page
will list the factors which may determine the judgment on the propriety of any
particular research protocol. These factors can be divided into two categories:
Those whose application is relatively straightforward and those where line-drawing
problems can arise most easily. This distinction is essential for my conclusion,
which is that a different kind of safeguard must be established for the two types
of factors. For the distinctions easily made, requirements can be stated and
ascertained by Human Studies Committees, and abuses spotted. For the dimensions
where there are line-drawing problems, on the other hand, it will be necessary
to err far on the "safe" side, so that no dangerous spread takes place, and so
that individuals do not unwittingly commit acts for which they can be found
liable.
IV. SHOULD THERE BE ANY RESEARCH ON FETUSES NOT FOR THEIR OWN BENEFIT?
1. The Argument for Rejecting All Such Experiments
The main categorical objections to all such experiments come from those
who hold that fetuses are human beings entitled to life and to consent. Their
argument takes this form:
Premise 1 - The fetus is demonstrably a human being.
Premise 2 - Experiments should be performed on human beings only with
their consent or with that of others having a concern for
their safety.
Premise 3 - Mothers who intend to have an abortion clearly have no
concern for the safety of their fetuses, and are thus
incompetent to give consent to research involving these
fetuses .
2-3
DIMENSIONS OF FETAL RESEARCH
Application Relatively Clear-Cut
1 . Intended Fate of Fetus
Definite support (no abortion
planned
Definite abortion
Conditional abortion (e.g., after
antenatal diagnosis)
2. Actual Fate of Fetus
Birth
Spontaneous abortion
Induced abortion
3 . Person Doing Research
Physician in charge of pregnancy
Another investigator
Others (mother, etc.)
4 . Intended Beneficiary
Fetus (subject of experiment)
Fetus (subject of experiment) ,
depending on diagnosis
Future individuals
No beneficiary now foreseen
5 . General Purposes
Therapeutic
Diagnostic
Other (use of tissues, learning
techniques, etc.)
6. Consent Given By
No one
Mother
Father
Local Human Studies Committee
National Ethics Committee
7. Research Planned for Fetus
Before pregnancy
During pregnancy
During labor
After labor
8 . Research Intervention Initiated
Before beginning of labor
During labor
After end of labor
9 . Conclusion of Intervention
Before beginning of labor
During labor
After end of labor
Giving Rise to Line-Drawing Problems
a. Degree of Viability
None, given present state of
l<nowledge and available means
of support
Marginal
High
b. Rislt of Harm to Fetus
High
Moderate
Low
Unltnown
Nonexistent
c. Ris}t of Pain for Fetus
High
Moderate
Low
Unknown
Nonexistent
d . Risk of Harm to Mother
High
Moderate
Low
Unknown
Nonexistent
e . Risk to Others (Newborns, Society,
Medical Profession, etc.)
High
Moderate
Low
Unknown
Nonexistent
f . Validity of Research Design
High
Doubtful
Nonexistent
g. Potential Usefulness of Results
of Research*
Strong
Moderate
Low
Unknown
Nonexistent
*A number of separate dimensions are involved here, such as immediacy with which the
new information can be applied, number of persons it can help, degree of suffering
or inconvenience which can be avoided.
2-4
Premise 4 - The same is true of any investigator wishing to involve a
fetus in research not for its benefit.
Conclusion - Therefore, experiments should be performed on fetuses,
when they themselves cannot be benefitted, only if they
can give consent.
Practical - Since fetuses clearly cannot give consent, no such
Consequences research should be done where they are subjects.
This argument is too sweeping in its conclusion. It relies uncritically
on the vague notion of "humanity"; when closely examined, it cannot support the
conclusion or its consequence of excluding fetal research.
2. The Premise of Fetal Humanity
"The temptation to introduce premature ultimates - Beauty in
Aesthetics, the Mind and its faculties in Psychology, Life in
Physiology, are representative examples - is especially great
for believers in Abstract Entities. The objection to such
ultimates is that they bring an investigation to a dead end
too suddenly."
^' ' -' ," -I. A. Richardsis
In discussions about the fetus, the premature ultimate is "humanity." Does
the fetus possess humanity? When in the life of a cell or of fetal life does
humanity begin? What rights go with such possession? ''•'•^"•i^''^''®'^"
These and similar questions have arisen beginning with the earliest specula-
tions about human origins and characteristics. But they cannot help us come to
grips with the problems of abortion and fetal research; instead they short-circuit
all discussions in these domains and lend themselves to superficial interpreta-
tions precisely because of their obscurity.
For the various views as to when humanity begins do not depend upon factual
information. Rather they are representative of different world views, often of
a religious nature, involving deeply held commitments with consequences for
action and policy.
The Supreme Court opinions on abortion have already declared that the fetus
has no legal personhood, thus no right to give consent .i*'i8 For many, this per-
mission to abort without fetal consent suffices to permit experimentation without
such consent as well, wherever an abortion is planned or has taken place.
I should like to present an analysis which could support the Supreme Court
view insofar as early abortions are concerned, while finding strong reasons to
be much more cautious with respect to later pregnancies. In order to do so, it
is necessary to ask what are the reasons underlying the protection of human life,
and then to see whether these reasons are present in early pregnancy.
A failure to scrutinize these reasons lies at the root, not only of the
confusion about abortion and fetal research, but of the persistent vagueness
and consequent abuse of the notion of "respect for life." The result is that
everyone, including those who authorize or perforin killings of civilians and
bombardments of hospitals, can and do profess their belief in life's sacredness.
I shall try, therefore, to list instead the reasons which underlie the elemental
sense of the sacredness of life, reasons concerning the meaning which a threat
of harm can have to the victim, to the agent, to those who care about the vic-
tim, and to the community at risk from the spread of such harm:
a. For the victim, harm and/or killing:
(1) If anticipated, causes intense anguish, fear, and a sense
of loss of all that can be experienced and valued in life,
(2) Can cause great suffering,
(3) Can unjustly deprive those who have begun to experience
life of their continued experience thereof.
b. For the agent, killing and harming others can be brutalizing
and criminalizing. It is not only destructive to the agent,
therefore, but a threat to others.
c. For the family of the victim and others who care there can be
deep grief and loss. They may be tied to the victim by affec-
tion or economic dependence; they may have given of themselves
in the relationship so that its severance causes deep suffering.
d. All of society, as a result, has a stake in the protection of
life. Permitting killing and harm sets patterns for victims,
agents, and others, that are threatening and ultimately harmful
to all.
These are principles that underlie the protection of life. They are shared
by those who reflect upon the possibility of being harmed or dying at the hands
of others. If these principles are applied in the absence of the confusing
terminology of "humanity," they rule out the institutionalized killing perpetrated
in bombings of hospitals and villages, as well as in witch-hunts and racial perse-
cution. The victims of these acts fear death and the suffering of dying; their
survivors grieve; and the societies engaging in such acts are brutalized and
degraded. Similarly, these principles would rule out experimentation on infants,
children and adults without the strictest safeguards for consent and safety.*
♦Ramsey 13 resorts to an analogy between research without consent upon the fetus
and upon those condemned to death, or dying, or unconscious. It is clear, how-
ever, that the analogy is very weak, precisely because the principles which I
have listed would rule out research on these individuals without lawful consent.
Turning once again to abortion and fetal research, how do these principles
apply to the risk to life in the first weeks of gestational age? Consider the
very earliest cell formations a few days after conception. Clearly the reasons
for protecting life fail to apply here.
This group of cells cannot feel the anguish or pain connected with death,
nor can it fear death. Its experiencing of life has not yet begun; it is not
yet conscious of the interruption of life nor of the loss of anything it has
come to value in life. Nor is it tied by bonds of affection to others. If the
abortion is desired by both parents, no grief will be caused such as that which
accompanies the death of a child. Almost no human care and emotion and resources
have been invested in it. Nor is such an early abortion and consequent research
brutalizing for the person voluntarily performing it, or a threat to society.
Because there is no semblance of human form, no conscious life or capability to
live independently, no knowledge of death, no sense of pain, words such as "harm"
or "deprive" cannot be meaningfully used in the context of early abortion and
fetal research.
The reasons to preserve life, therefore, are absent in the early stages of
gestational age;* as a result, the argument opposing all fetal research because
of the humanity of fetuses fails. The word "humanity" has been used as a "pre-
mature ultimate" in the words of Richards. Moreover, it has different meanings,
in terms of the reasons to protect life, in early unwanted pregnancies as dis-
tinguished from other contexts.
Because this premise of early fetal humanity fails to apply, the second pre-
mise of the argument set forth on page 2-3 concerning fetal consent is invalid
as well, as is the conclusion and its practical consequences of ruling out all
fetal research of the kind discussed.
A. Fetal Consent
For the reasons stated, then, fetal consent is not required. It ought
not, therefore, to be an issue in the discussion; and it is unnecessary to group
fetuses with prisoners, children, and the institutionalized, whose competence
to consent or freedom to do so is in question, and where there is special need
for protection.** Whatever "consent committees" or other protective mechanisms
are worked out to provide protection of such a nature should not be required also
in the case of early fetal research.
*As for research early in pregnancy on fetuses which are not to be aborted,
every effort must be made to see that they arrive unharmed to the point where
all the reasons to preserve life will operate fully. Even from the earliest
moments of a wanted pregnancy, however, the third reason operates — attachment
to the child to be born, and grief and worry at the thought that it might be
harmed.
**See DHEW Proposed Policy, August 23, 1974. 12
2-7
B. Maternal Consent
For the same reason, the need for proxy or third-party consent by the
mother is also basically unnecessary as far as the fetus is concerned. Neverthe-
less, I believe that a conflicting force enters in here, rendering the request
for consent from the mother mandatory. If the mother acknowledges that the fetus
may have a right to live, though not a right to live attached to her, then she
may well be pained at the thought of dissection or autopsy or other experimenta-
tion on the fetus; 21 it seems right, under such circumstances, to give her the
option of not consenting to fetal research even after the abortion.*
Maternal consent is desirable, then, for all fetal research, even that
begun only after an abortion. But it is most clearly required in all those
studies initiated before or during pregnancy, so as to avoid the possibility of
any mistake and because the procedure may affect the pregnant mother herself.
(Consent by the father, on the other hand, while doubtless something which would
be taken for granted in a close relationship, ought not to be required, just as
it is not required for abortion itself. )2
C. Maternal Consent to In Utero Research
If a pregnant mother, planning to have an abortion, consents to an
experiment involving some risk to her fetus, and initiated before the abortion,
then several problems may arise:
(1) It will be harder for her to change her mind about the abortion,
should she wish to do so. Yet, no one should be forced, or even mildly coerced,
into an abortion. She may feel there is now a new reason — possible fetal
damage — added to her previous reasons for wishing to have an abortion, even
though these previous reasons — say an unhappy marriage or an illness--may no
longer be present. And, she may feel that she, by consenting to the experiment,
is somehow "under contract" to have the abortion; that she might disappoint the
investigator and impede "science" by changing her mind.
(2) Her pregnancy may be unduly prolonged. If the investigator wants
to study the effect of a drug, for instance, given to the mother ten days or
two weeks before an abortion, her pregnancy may have to last that much longer.
This is even more risky as the interval lengthens or as the research takes place
later in pregnancy. This is most undesirable, from the point of view of increased
mortality and morbidity associated with late abortions.** It is also undesirable
from a moral point of view, as an early abortion is in itself a more justifiable
act than a late abortion, given the reasons to protect life listed on page 2-6.
*I strongly disagree, therefore, with the suggestion in the British Report on
Fetal Research that asking for maternal consent should not be required since
it could be an iinnecessary source of distress to the mother. No empirical
evidence suggests that such is the case; should there be such concern for a
particular mother, it would be better not to use her fetus in a study.
**See C. Tietze, Induced Abortion, A Factbook.22
In those experiments undertaken so late that the actual abortion is delayed past
the eighteenth week, real problems having to do with the borderline between non-
viability and viability will arise.
Very few women would voluntarily submit to carrying an unwanted pregnancy
past that point if they could abort earlier. The explanation for the fact that
experiments have been done at that late time in pregnancy, in Scandinavia, for
example, is that, up to recently, it was so difficult and time consuming to
obtain permission for abortions that women were often forced to wait past the
trimester. With changing abortion laws, the availability of late pregnancies
for experimentation and subsequent abortions may be expected to diminish dras-
tically.
As a result, I believe that all experiments initiated during pregnancy in
anticipation of abortion should be subjected to the strictest regulation, though
I do not advocate that they be ruled out. Such regulation could be carried out
by a local Committee on Human Experimentation, keeping the following safeguards
in mind :
- Experiments should take place, if at all, as early in pregnancy
as possible, and those experiments which delay abortions past
the eighteenth or twentieth week ought to be ruled out.*
- The investigator ought not to be the physician in charge of the i^
pregnancy or abortion.* And all decisions about the pregnancy
ought to be made independently of the needs of the experiment.
Thus, the timing of the abortion, the method used in the abor- ■;,,:
tion, and other factors should not interfere with requirements :. .:,.,.■::
for maternal safety and well-being.
- Women who are hesitant about wanting an abortion should not be . ■
asked to participate in fetal research. c .::a,5. ■ , ,:
- Drugs given should have been accepted as safe for adults. -3.!'
- All elements of informed consent should be carefully attended to.
- Mothers should be allowed to withdraw from the experiment at any
time, and to change their minds about going ahead with the abor-
tion.
- Insurance for harm to the baby through the research should be
available should the mother decide to carry on with her pregnancy. ;■:_.'
- Carelessly planned experiments, incapable of yielding valid
results, should be ruled out.**
*With the exception of experiments done to benefit the fetus or its family, as
in antenatal diagnosis.
**Sut:h experiments are, in my opinion, also highly questionable when, as is often
the case, they are performed upon animals, and involve suffering. 2.24
2-9
- Experiments which might induce women to become pregnant in order
to submit them to research unrelated to their needs or those of
their fetus should be ruled out.*
These safeguards** would protect women against the two dangers mentioned:
that of possible coercion to go ahead with an abortion no longer wanted, and
that of a prolongation of the pregnancy for the sake of the research but to the
detriment of the mother. With such safeguards, important experiments, such as
that which established the risk to the fetus of vaccinating a pregnant woman
against Rubella, would continue to be possible.
D. Other Forms of Consent
Similar consent by local Committees on Human Experimentation should be
required for all research involving living fetuses. For all research, these
committees should debate carefully whether all safeguards against abuse and
spread to late pregnancy and abortion are provided. (These safeguards will be
discussed in Parts V and VI.) Finally, such Committees must safeguard the
interests of the pregnant women, over and beyond the point at which they them-
selves have given consent to participating in such fetal research as affects
them.
The answer to the question whether there should be any experimentation on
fetuses which is not in their own interest can, therefore, be "yes." At least
some experimentation consistent with the safeguards listed can be undertaken in
order to seek knowledge not otherwise available. Fetal consent is irrelevant,
while maternal consent and careful study of each protocol by institutional Com-
mittees on Human Experimentation are required.
Moreover, as long as the nontherapeutic research in question involves a
risk, it ought to be undertaken only on abortuses or fetuses which are to be
aborted. In much experimentation, the time comes to test a new measure on
individuals who may not themselves benefit therefrom. It is an agonizing pro-
cess to decide how to go about this and how to provide for appropriate consent,
especially in the case of children, where consent is already so problematic. s
It is only in the case of abortuses or fetuses about to be aborted that this
question of consent does not come up. Therefore, there is a clear obligation
to do all research which has to be done upon them, rather than upon those for
whom no abortion is planned.
*Such experiments are, in my opinion, also highly questionable when, as is
often the case, they are performed upon animals, and involve suffering.
*These safeguards will be seen to relate to the dimensions listed in the
Chart on page 2-4 numbered: 3,6, 2, 7,8,9 ,b,d, f .
V . WHAT SAFEGUARDS ARE NEEDED?
Even if it is agreed that some forms of early nontherapeutic fetal experi-
mentation should be permitted, the problem of how to prevent an undesirable
spread of such research will arise. Clearly, it cannot be permitted on infants,
children and adults without stringent protection and provisions for consent.
Where, then, must a line be drawn which protects society against a spread of
nontherapeutic research which could endanger newborns and children, and ulti-
mately all of us? And how can we be sure that such a line won't be crossed?
1. What Risks are of Concern? What Dimensions are Involved?
In order to answer these questions, it is necessary to look once more at
the chart on the Dimensions of Fetal Research, and at the factors according to
which different kinds of fetal research can vary. Those factors which are
ethically relevant and capable of clear-cut distinctions have already been lim-
ited by the safeguards suggested on pages 2-9 and 2-10. Others are more fluid
and therefore possess features presenting special line-drawing problems.*
The risks which are of greatest concern are those in that fluid category.
They are the risks to society which could stem:
a. From moving along the continuum of experimenting on the previable
and, then, the viable fetus without intending to benefit it, but
rather others;
b. From the brutalization which could stem from any evidence that
substantial pain is inflicted on fetuses in such research;
c. From the brutalization of the participants in such research and
of the public which could come from using fetuses near viability.
All these risks are real, I believe, unless fetal research is restricted so
as to take place only well before viability (unless, as mentioned earlier, the
health of the fetus itself is at stake) .
2. Viability
It is well known that viability is a fluid and shifting concept, dependent
not only on the state of knowledge at a particular location where a birth or
abortion takes place. is, 23 ^ fetus that has a 1 in 100 chance of living, therefore,
*I have described 3 the ways in which such fluid dimensions sometimes present
possibilities for a "slippery slope" or "entering edge of the wedge" develop-
ment, and the conditions which encourage or prevent such a development.
2-11
or a 20 in 100, or an 80 in 100, ought not to be experimented upon non therapeu-
tically, because of the real danger of a slippery slope development. I would
recommend that the United States, at the very least, follow the guidelines set
by the Peel Commission in Great Britain:^^
2. The minimal limit of viability for human fetuses should be
regarded as 20 weeks of gestational age. This corresponds
to a weight of approximately 400-500 grammes.
4. The use of the whole previable live fetus is permissible
provided that: "ii. only fetuses weighing less than 300
grammes are used."
It would be preferable, I believe, given the difficulties of determining
gestational age, and the possibility of mistaken estimates, to use the lower
weight in paragraph 4 above as well as the gestational age of 18 weeks as a safer
cutting-off time in fetal research. In addition, for experimentation undertaken
in utero, on mothers with the intention to abort, the experiment should not be
undertaken unless the abortion can take place during the first 18 weeks. Natu-
rally, these restrictions should be reviewed at regular intervals so as to remain
consistent with advances in supportive techniques and special policy. 2
With such a limitation in gestational age, I believe that the risks of:
a. Experimenting on the viable fetus,
b. Causing pain to the fetus, ;
c. Brutalizing participants and society,
can be avoided altogether.
3. Dangers To Society
The following argument is often advanced against such a conclusion. It
holds that we must guard against even the least likely threats to our society
which could come from a spread of fetal research, by banning it altogether.
Infanticide, euthanasia, cruel experiments without consent of the kind perpe-
trated in Nazi concentration camps--these are all held out as possible and more
likely once we allow abortion and fetal research. Such an argument in fact, then,
advances the fourth reason for protecting life* as crucial even with respect to
fetal research in the first weeks of gestational life — that to take such lives
would pose threats to all of society.
It is important to see here the distinction between a logical and a factual
argument concerning the risk of undesirable consequences from permitting fetal
*See page 2-6.
2-12
research. The logical argument holds that since no clear line can be drawn in
gestational age between newly conceived humans and newborns, we endanger the
rights of newborns by permitting inroads on the rights of fetuses. This argu-
ment has failed to convince many responsible members of our society including
a majority of the Supreme Court. And a consideration of the reasons for sup-
porting life, outlined in Part III of this paper, shows that distinctions can
be made which permit abortion and fetal research up to a point in gestational
age, but not thereafter.
This logical argument, however, is often confused with a factual argument,
holding that fetal research will in fact predispose doctors, researchers, or
society as a whole to violate the rights of children and other persons. It is
clear, however, that such a factual argument is only as good as the facts on
which it relies for evidence.
Taken as an empirical argument, it must be seen for what it is--an inflam-
matory toying with human fears totally unrelated to any development seen to have
taken place in societies permitting abortion and fetal research. To the best
of my knowledge, available data do not bear out such dire predictions. The
societies which have permitted abortion for considerable lengths of time have
not experienced any tendency to infanticide, euthanasia, or Nazi-style experi-
ments on children or adults. The infant mortality statistics of Sweden and
Denmark, for example, are extremely low, and the protection and care given to
all living children, including those born with special handicaps, is exemplary.
It is true that facts cannot satisfy those who want a logical demonstration that
dangerous developments cannot under any circtimstances come about. But if they
are also trying to warn of actual risks, the burden of proof rests upon them to
show some evidence of such developments taking place before opposing a policy
which will mean so much to children and their families, and also to show why it
would not be possible to stop any such development after it begins to take place.
The fear of slipping from abortion and early fetal research towards infan-
ticide, therefore, is not supported by any available evidence. It ought no
longer to be exploited for political purposes.
4 . Fetal Death - ■ ' . - .
Within the first 18 weeks of gestational age, ought researchers to be
permitted to attempt to keep fetuses wholly or partially alive for a period of
time, even though there is no chance that they might live permanently? And,
secondly, ought researchers be permitted to take action which could in any way
bring about death of such a fetus? The British Peel Commission allows both of
these, given all other safeguards .25 The proposed DHEW guidelines 12 limit the
first and rule out the second:
46.307 (d) Vital functions of an abortus will not be artificially
maintained except where the purpose of the activity is
to develop new methods for enabling the abortus to sur-
vive to the point of viability and
(e) Experimental procedures which would terminate the heart-
beat or respiration of the abortus will not be employed.
Because of the absence of the reasons to protect fetal life in the early
weeks of gestational life, I believe that these DHEW restrictions are unneces-
sary. The permission granted by the Peel Commission is to be preferred, so long
as all safeguards including the time limitation are observed. In exceptional
circumstances, (d) should be permitted even after such a time limit, so long as
the greatest care is exercised to avoid pain to the fetus and to protect any
fetus capable of surviving such a process.
5. Experimentation and Therapy
Much of this paper has dealt with research done upon a fetus in order to
benefit, not that fetus, but other fetuses and babies, even adults. But it is
important to consider also the kind of experimentation which is conducted in
hopes of benefiting the fetus, the mother, or the "maternal-fetal unit". Here,
of course, the strictest guidelines for consent and protection of subjects must
obtain. But a great deal of haphazard experimentation is conducted without such
high standards, where physicians experiment with the care they give to pregnant
mothers, using different diets, drugs, and procedures, without relying on valid
documentation or setting up scientifically valid protocols submitted to Human
Studies Committees. Similarly, mothers often engage in experimentation of the
same kind, perhaps without the benefit of medical advice at all. I believe that
the most important task in protecting fetuses is to stress the risks to which
they are subjected through such casual experimentation and therapy. And it is
through fetal research that we are coming to know just how great these risks are,
and learning to forestall them.i^
In addition to such casual experimentation and therapeutic practices, there
are also many experiments done to study pregnancy and its processes without a
real understanding of the fact that fetuses can be harmed thereby. Studies
altering the metabolism of pregnant mothers, for instance, must clearly affect
the fetuses as well. We must severely restrict such experiments, therefore, and
not allow many of the routine studies performed on pregnant mothers until we can
be sure they have no harmful effect on the fetus.
VI. CONCLUSIONS
Some have argued that the babies who will suffer and die from the illnesses
which fetal research could have alleviated or cured are not properly speaking
the responsibility of those who wish to ban such research. They hold that no
matter how important the ends are, evil means cannot be employed to reach them.
This refusal to take responsibility for the illness and death which could be
alleviated through research becomes untenable, however, when the means are
shown not to be evil, as I hope to have shown in this paper.
A combination of a ban on fetal research protocols and the continued casual
therapy and experimentation in medical practice and self-medication would mean
a reckless abandon of foresight for our society. Far more moral and humane, I
believe, is a program of carefully planned experimentation with proper safe-
guards , combined with a renewed caution in treating and supporting pregnant
mothers and newborns.
A Commission genuinely concerned to protect fetal and childhood develop-
ment, therefore, could make a great difference for health and well-being by
issuing a strong statement:
- Setting forth the risks to fetuses from improper maternal use of
drugs, sprays, creams and harmful procedures;
- Calling for a halt on drug use (including nicotine and alcohol)
not shown to be clearly needed by women who might be pregnant;
- Calling on health professionals, drug companies and pharmacists
to exercise leadership and genuine concern in these respects;
- Setting forth a coordinated policy of fetal research with the
following safeguards:
1. That all experimentation on a viable or marginally viable
fetus over 18 weeks of gestational age or 300 grammes in
weight, be ruled out.
2. That the only exceptions to such a ban, where permitted by
a hospital Human Studies Committee, be:
(a) Those research protocols which seek to benefit the fetuses
used as subjects or their families.
(b) Those protocols which seek to develop new techniques for
helping prematurely born infants to survive.
(c) Those protocols which seek to test new diagnostic tech-
niques not possible at an earlier gestational age.
3. That approval of experiments be sought from Local Human Studies
Committees passing on the nature of the consent, the validity
of the research, the competence of the investigators, the avail-
ability of alternative kinds of research, and the risks and
benefits involved.
4. That consent be sought from mothers of the fetuses studied,
and no pressure be exercised in favor of abortion.
5. That the earliest possible time in pregnancy be sought for
all such research.
6. That compensation be available to mothers having agreed to
research in anticipation of an abortion, should they change
their mind and give birth to a baby harmed by the research.
2-15
7. That methods of abortion and determination of gestational age,
weight, and viability rest with attending medical personnel
rather than with the investigator (except for 2a above) .
8. That no drugs be administered, or procedures undertaken during
pregnancy which are known to be harmful to fetuses and/or others.
9. That no experiments be undertaken which might induce mothers
to become pregnant purely for experimental purposes.
10. That these safeguards be periodically reviewed.
2-16
REFERENCES
1. "An Act Prohibiting Experimentation on Human Fetuses," Chapter 421, General
Laws of Massachusetts, approved 26 June 1974.
2. Bok, S., "Ethical Problems of Abortion," Hastings Center Studies 2 (No. 1) :
33-52 (to appear also in #19 below) .
3. Bok, S., "The Leading Edge of the Wedge," Hastings Center Report, December
1971.
4. Bok, S., "Who Shall Count as a Human Being? A Treacherous Question in the
Abortion Discussion," in Abortion: Pro and Con, Schenckman Piiblishing
Company, 1975.
5. Capron , A.M., "Legal Considerations Affecting Clinical Pharmacological
Studies in Children," Clinical Research 21: 141-150, February 1973.
6. "Fetal Research: The Case History of a Massachusetts Law," Science
187:237-241, January 24, 1974.
7. "Fetal Research (II): The Nature of a Massachusetts Law," Science
187:411-413, February 7, 1975.
8. Fleet, William F., Jr., et al, "Fetal Consequences of Maternal Rubella
Immunization," JAMA 227 (No. 6) : 621-627, February 11, 1974.
9. Langer, W. , "Infanticide: An Historical Survey," History of Childhood
Quarterly 1 (No. 3) : 353-366, Summer 1974.
10. Noonan, J.R., Jr., (ed.) The Morality of Abortion, Cambridge, Massachusetts:
Harvard University Press, 1970.
11. Noonan, J.T. , Jr., "Responding to Persons: Methods of Moral Argument in
Debate Over Abortion," the Eighteenth Annual Robert Cardinal Bellarmine
Lecture, delivered at St. Louis University School of Divinity, November 5,
1973.
12. "Protection of Human Subjects," Department of Health, Education and Welfare,
Federal Register 39 (No. 165), August 23, 1974.
13. Ramsey, P., The Ethics of Fetal Research, New Haven: Yale University Press,
1975.
14. Reback, G.L., "Fetal Experimentation: Moral, Legal and Medical Implications,
Stanford Law Review 26: 1191-1207, May 1974.
REFERENCES (Continued)
15. Richards, J.A. , Principles of Literary Criticism, London, 1925.
16. "Scientific Freedom and Responsibility," a report by the AAAS Committee,
September 1974.
17. Shaw, A., "Dilemmas of 'Informed Consent' in Children," New England Journal
of Medicine 289 (No. 17): 885-980, October 1973.
18. Supreme Court of the United States, Doe et al. v. Bolton, Attorney General
of Georgia, et al., 1973.
19. Supreme Court of the United States, Roe et al. v. Wade, District Attorney
of Dallas County, 1973.
20. Talbot, N. , (ed.) Raising Children in Modern Urban America, Boston: Little,
Brown Publishing Company, forthcoming.
21. Thomson, J., "A Defense of Abortion," Philosophy and Public Policy 1: 47-66,
1971.
22. Tietze, C. and Dawson, D.A. , "Induced Abortion: A Factbook," Reports on
Population/Family Planning, The Population Council, New York, December 1973.
23. Tribe, L. , "Foreword: Toward a Model of Roles in the Due Process of Life and
Law," Harvard Law Review 87: 1-54, 1973. (A comment on the Supreme Court's
decisions on abortion.)
24. Tribe, L. , "Ways Not to Think About Plastic Trees: New Foundations for
Environmental Law," Yale Law Journal 83 (No. 7) : 1315-1348, June 1974.
25. "The Use of Fetuses and Fetal Material for Research," Department of Health
and Social Security, Scottish Home and Health Department, Welsh Office,
Report of the Advisory Group, Her Majesty's Stationery Office, London, 1972.
26. Walters, L. and Goldstein, D. , (eds.) "A Bibliography on Experimentation and
the Fetus," The Joseph and Rose Kennedy Institute for the Study of Human
Reproduction and Bioethics, November 1974.
27. Walters, L. , "Ethical Issues in Experimentation on the Human Fetus, Journal
Religious Ethics 2 (No. 1): 55-75, 1974.
2-15
FETAL RESEARCH:
AN ETHICAL APPRAISAL
Joseph F. Fletcher, S.T.D.
JOSEPH F. FLETCHER, S.T.D.
Dr. Fletcher is presently Visiting Professor of Medical
Ethics at the University of Virginia.
PD 304109-5
Fetal Research:
An Ethical Appraisal
We want our people, especially our children, to be safe from genetic and
congenital disorders, uterine infections, and a host of other maladies. This
means we have to learn as much as we can about controlling reproduction, for
the security and quality of human life and well-being, and to be free as much
as possible from the dangers of blind, natural cause and effect. Individual
scientists, in addition, of course, may be moved by an intellectual itch and/or
a hunger for fame.
How can we continue to achieve enormous research benefits for reproductive
medicine, while at the same time maintaining a high ethical standard of concern
for human subjects? It will be contended in this appraisal that fetuses are not
"human beings" in the nonbiological sense of persons, even though they are poten-
tially persons. What, then, do we owe them?
What the reasons are for an increased concern about this in the past ten
years are not at all clear, or at least not aboveboard. In the past "age of
faith" this concern was not very strong or well articulated. It has arisen
among research scientists and physicians themselves; they have called in lawyers
and ethicists and psychologists to explore it. It is reflected in the monitoring
procedures of NIH, FDA and NSF, in the peer review law (PSRO) , and in generally
normative practice. The public's attention has been alerted by organ transplants
(especially hearts) , the thalidomide disaster, and by scandalous episodes such as
the Tuskegee syphilis affair and the South-Mandel case of cancer cell research in
New York. ^
Nonetheless, the need of more knowledge remains, and perceived needs pro-
liferate as the knowledge accumulates. Virtually all that is known of some
branches of reproductive medicine has come from clinical research; assets such
as antenatal diagnosis, furthermore, have been acquired through fetal research
in utero. The Nuremberg code is definite: clinical experimentation is justi-
fied if it can yield "fruitful results . . . unprocurable by other methods and
means . "
One survey of attitudes has reported that clinical researchers are "low"
on ethical concern. They had put the question, "What characteristics do you
want to know about another researcher before entering into a collaborative
relationship . . . ?" The response was 86 percent "scientific ability,"
45 percent "hard work," 43 percent "personality," and only 6 percent "ethical
concern for research subjects."^ The respondents, it should be noted, were
first of all concerned for competence because that is their first ethical obli-
gation to their subjects. "If you have to do it, do it well." The fact that
"concern for research subjects" does not leap to mind certainly does not mean
they care nothing about their subjects, as any very wide acquaintance with phy-
sicians will show.
3-1
ETHICAL PRINCIPLES AND PREMISES
People often think that ethics means finding something that is "bad," as
such, and then categorically forbidding it by a rule of morality. This is indeed
one kind of ethics. However, in this appraisal, as John Dewey would have called
it, a hypothetical rather than a categorical ethics will be employed. In this
kind of ethics the moral agent says, "If you do not want such as such, then
because of its consequences this or that is wrong." Rightness and wrongness are
judged according to results, not according to absolute prohibitions or require-
ments. The ethics in this appraisal, therefore, is not categorical, based on
prescriptive norms; it is not ideological nor rule-determined. On the contrary,
it is based on the principle of proportionate good; it is consequential, prag-
matic, and value-determined.
To illustrate, neither amniocentesis nor fetoscopy is as yet entirely with-
out risk as a diagnostic procedure — there is some risk in the aspiration of amni-
otic fluid and in the use of cannulas and lens to examine fetuses suspected of
being aberrant or diseased; for example, getting blood samples in a suspected
hemoglobin disorder like beta-thalassemia. The procedure is still experimental,
still investigative medicine. One state's law bans it as nonbenef icial risk to
a live fetus. Yet three out of four times such a diagnosis would yield "all is
well" or "signs negative" — a preponderantly good consequence. In this appraisal,
therefore, it is held to be a good thing, because it eliminates the risk of ter-
minating healthy pregnancies out of fear of getting a defective baby.
This particular law was passed on the ground that all nonbenef icial risks
to a fetus are wrong as such, regardless of whether we could weigh up the bene-
fits and discover that in some cases they more than make up for whatever the
risks and costs might be. The fact that it would save many babies is not, in
doctrinaire ethics, allowed to weigh against the categorical condemnation. It's
followers would say, "All experimental risks to live fetuses are ipso facto
unethical, no matter how good the consequences." (One religious moralist has
even argued, in addition, that it is unethical because the fetus has not given
its consent nor ever could — rather like those who condemn abortion, regardless
of any good consequences to be gained.)
Pappworth puts it very bluntly. "Whether an experiment [has] gained its
desired result or not is to me immaterial .... A worthy end does not justify
unworthy means .... Every human being has the right to be treated with
decency and that right belongs to each and every individual and should supersede
every consideration of what may advance medical science. No doctor is justified
in placing science or the public welfare first and his obligation to his patient
second."-' (His italics.) Here we have a whole battery of ethical assertions,
all of which will be rejected or seriously qualified in this appraisal: his
radical individualism, the notion that the end cannot ever justify the means,
an appeal to "rights" as if they were perfect and unconditional, and an undis-
closed but obviously quite subjective understanding of "decency."
This brief discussion of ethical alternatives shows how a pragmatic ethics
based on values, quality of life, and proportionate good, differs from a dogmatic
ethics of rules and categorical judgments and prejudicial decision making. It
also helps the reader to know what ethical "rules of the game" are being followed
here. Now let us turn to the question itself, as it is analyzed by an ethicist
who is neither a biologist nor a physician.
The core question at stake in the ethics of fetal research is whether a
fetus is a person. Very soon after fertilization it is apparent that the con-
ceptus or embryo is biologically of the human species, and that it is living in
the sense that cell division is going on furiously. But are we to assign per-
sonal status to a fetus, i.e., render it the regard and rights we grant to living,
breathing, independently functioning individuals? The contention that we should
assign human rights to the fetus is a familiar one, but definitely rejected by
the Supreme Court. In Roe v. Wade (1973) it decided this question at last in
terms which uphold the ethics of relative values — namely, that fetuses are not
persons, although any state may (but not must) choose to protect fetal life from
termination in some cases in the third trimester, out of a "compelling interest"
in the potential (postnatal) person. ■* The Court itself, then, did not proscribe
even third trimester abortions, as in such procedures as hysterotomies and saline
induction — prior to viability. The logic of the decision is to validate not only
terminating pregnancies by the induced abortion of previable fetuses but the
forestalling of unwanted live births late in pregnancy — undesirable as it might
be medically in most such cases.
An actual person, as distinguished from a potential one, is therefore both
legally and ethically a human being who has left the maternal/fetal unit, is born
alive, and lives entirely outside the mother's body with an independent cardio-
vascular system. Only the pregnant patient is a "human subject" to be protected
in clinical experimentation and research; the fetus is an object, not a subject —
a nonpersonal organism.
A fetus is "precious" or "has value" when its potentiality is wanted. This
means when it is wanted by the progenitors, not by somebody else. Hence the prin-
ciple of privacy, of one's control of one's own body and its product — except that
some states might intervene to do the wanting after 24 weeks of gestation. The
courts have held further that if a fetus is wanted by one progenitor but not the
other, then the mother has the initiative, either to carry it to term or to
abort. (This last problem does not arise for asexual reproduction like cloning.)
The metaphysical or religious belief that fetuses are persons is a per-
fectly legitimate act of faith but there is no way to prove it or show it (no
litmus paper test, so to speak); by reason of its nonempirical nature as a faith
assertion it cannot be either verified or falsified. Most of us, when we look
at the consequences of that belief, reject it because of what consistently acting
on it would mean for the quality of life in our children and the standards of
reproductive medicine. To treat live fetuses as "untouchable" is absurd; vari-
ables such as their functional condition and health prospects, costs of treatment
both financially and emotionally, maternal consent, the need to "touch" them,
whether they are destined for termination — these factors should enter into the
decisional mix.
3-3
The fetus is not a patient. A patient is a person. The Hippocratic Oath
does not recognize the fetus as a person — unless you want to infer it from the
archaic statement, "I will not give to a woman a pessary to produce an abortion."
The World Medical Association's reduction of the Oath leaves it out altogether,
declaring only that the "utmost respect for human life from the time of its con-
ception" should be maintained — leaving open what "respect" and "conception" are
to mean .
Dr. Joshua Lederberg sees the problem in a nondoctrinaire way, as the great
majority do. Speaking of governmental proposals to limit fetus research, he
said, "The crux of the matter is whether one views the abortus [sic] as a per-
son . . . "^ He was replying to Dr. Andre Hellegers, a doctrinaire moralist of
the minority, whose contention was that "no one can give consent to an experiment
on [a live] aborted fetus .... It would be like asking consent from a parent
who had abandoned or battered a child. "^
Here we have a moral disagreement in good faith. One side thinks vitalis-
tically, that where there is fetal life there is a person; the other side deter-
mines personal status by quality of life. One group looks at persons as events
or endowments (e.g., "infusion of the soul") , while the other sees persons as
a process or achievement developmentally . This is clearly not a matter to be
decided by governmental fiat. The First Amendment to the Constitution forbids
any such solution in a pluralist democracy. In short, there should be no com-
pulsory pregnancy or motherhood, and by the same token no compulsory abortion
or fetal research.
The ethics of fetal research has had remarkably little discussion. For
example, in the 1,154 pages of the Katz compendium on the ethics and law of hxoman
experimentation-' there are fewer than a half dozen pages given to fetal research.
What we are to think about probing fetal life in utero and ex utero , in order to
prolong the life of children yet to be born or of children already born, is still
very much open to exploration and certainly open to differences of opinion and
practice. Physicians and scientists will have to decide pretty largely for them-
selves whether to learn how to save living human beings by the use of v/hole
fetuses, fetal tissues, or fetal materials. Each investigator, for example, will
have to decide for himself or herself whether — to take a couple of examples — to
perfuse fetuses to develop ways to prevent spontaneous abortions, or to prevent
drug toxicity in fetuses going to term. All should be free either to participate
or not to participate.
Expressed in philosophical language, as we have remarked, the question is
whether a fetus is an object or a subject. If, as we suppose here, the fetus is
not a subject, then it follows that "protection of human subjects" in fetal
research can only mean protection of pregnant women and live-born babies, pre-
term and full-term, not of previable fetuses in utero or ex utero.
A related issue is whether persons or subjects have to be actual or only
potential to be real — to be "in fact" human beings. The "error of potentiality"
is to confuse what is yet to be or could be with what is. It supposes that
because a fetus could possibly or probably become a person, it is therefore a
person now. Viability anticipated converts into viability realized. This
"prolepsis" falsifies reality; in its eagerness it slips into thinking that what
we want is already possessed, when in fact we are only hoping for it. In fact,
a fetus is precisely and only a fetus. ^
There seems to be good reason to question both the validity and usefulness
of the concept of viability, at least as a stage of gestation having any ethical
significance. Modern resuscitation and artificial life support technologies are
pushing "viability" farther and farther back towards nidation, possibly to four
weeks. Marginal errors about gestational age are inevitable, in spite of such
devices as ultrasound measurements of fetal head diameter. At present, infants
of 700 grams are probably the baseline, even though efforts are made to save
those of 600 grams if parents want it done.^ Yet research and development on
synthetic placentas and artificial uteruses is extending the incubation period
we now have for premature infants — prematurity having the greatest mortality
frequency in perinatal medicine. Viability is sure to be pushed back until its
relevance to speculations about humanness and personhood will have become absurd.
Those who are hung up on the "resemblance" of the fetal morphon to a live-born
baby will be released progressively from that psychological trap — called the
"homunculus reaction."
Such notions are always changing, as medicine's capabilities change. Via-
bility used to mean a fetus was capable of spontaneous functioning at separation
from the mother. Then it came to mean (for some, not all) being capable of func-
tioning by artificial means until spontaneous functioning begins. Soon it will
come to mean being kept going artificially at any stage beginning with fertil-
ization. Arguments about "prima facie viability" at 28 weeks or 24 weeks or
20 weeks are superficial and increasingly irrelevant to the question of surviva-
bility of fetal life. The good intention of one government official, who said,
"If you have a viable fetus you are in precisely the same position as you would
be with a minor child," is more and more taking on the appearance of the gro-
tesque.^ Throughout the centuries the term viability meant, literally, "ability
to live" — to live apart from maternal/placental support. No artificial support
was available. But now, with respirators and the new biochemistry of lung infla-
tion, who is to say what the word will come to mean, as to either the fetus'
development or its independence of the human uterus (ectogenesis) ?
The temporary guidelines recently laid down by NIH, trying to avoid the
pitfalls of viability's definition, made it a matter of simple heartbeat and
respiration, and then required that no "harm" be done to fetuses regardless of
head size, gram weight, physiological development, genetic diseases, congenital
anomalies — just whenever and simply because the heart beats and it breathes.
This disregard of quality-of-lif e factors is very upsetting; it is unacceptably
undiscriminating and inhumane. The question is not whether a fetus has vital
signs but whether it should be brought to live birth. If not, surely research
and experimentation are in order. A Tay-Sachs fetus in utero is alive; so is
a massively lesioned myelomeningocele prematurely expelled, ex utero. With
proper consent, learning from such false starts should be allowed as entirely
ethical, if in the first case abortion is chosen and if in the latter respiration
is foregone.
In America's pluralist society variety and difference of belief and values
are essential. They provide the creative abrasion of competition and inquiry.
Such disagreements, ethical as well as religious and cultural, are vital to the
progress of reproductive medicine, as they are to all other human enterprises.
Homogenization of opinion would be a disaster to science as well as to medical
care and treatment if any particular set of pre- or metaethical assiomptions about
personhood and humanhood in fetal life were to be given a monopoly force by law
or by funding work done exclusively according to only one system of ethics and
its rules for obstetrics, gynecology, perinatology, and pediatrics.
Quite apart from its being wrong to impose such rules, they would surely
be evaded and violated, thereby encouraging the dishonesty which always grows
up under a Big Brother and Authoritarian policy. Many people's belief propo-
sitions are entirely visceral, not rational — witness, for example, the repug-
nance some people feel at perfusion of a separated fetus head while feeling
none at the perfusion of its kidney. Where we start from is essentially impor-
tant in understanding our own moral judgments, and others', but to force us all
into the same value mold would be a moralistic dictatorship.
ETHICS IN FETAL RESEARCH
Our most searching ethical question has to do with live fetus research,
not the use of abortuses and fetal tissues and materials. After vital signs
are gone fetuses are in the domain of autopsy and pathological examination. The
issue is drawn by temporary regulations of NIH (DHEW) banning all nontherapeutic
live fetus research in utexo , whether the fetus is viable or previable, and even
if the fetus is destined for abortion and the research has the patient's consent.
These "regs" ban the use of artificial life support for research purposes, even
when a fetus is determined to be not viable, because it would be (obviously) non-
therapeutic and not to "save" the life of the fetus. ^°
Here we have an instance of a dogmatic or doctrinaire condemnation of some-
thing as intrinsically wrong, and regardless of any extrinsic consideration of
the benefits to be gained. Common sense, in any case, does not allow that a
fetus which is inviable or to be terminated can be "harmed" or "injured" or
"insulted," since acts of battery and mayhem presuppose a living, independent
individual biologically. Invasive treatment of a fetus, in either therapy or
experimentation, might come under the heading in law of mutilation, as of a
corpse, but would not be an injury (iniure or injustice) . An injustice predi-
cates a person. The only injury could be to the maternal patient, and with the
appropriate consent even that becomes null.
In a way NIH is therefore in the position of assigning "rights" to a fetus
in utero whether the patient wants the experiment or not. If, as this appraisal
maintains, a fetus is without personal status, the ban in effect assigns human
rights to a nonperson, which is precisely what the Supreme Court has set aside.
It is a repudiation of the judiciary by an agency of the executive. The legis-
lative branch of our government has also rejected the Court's judgment, by
endorsing a blanket denial of research funds, even though only temporarily, to
all live fetus research "unless such research is done for the purpose of assuring
3-6
the survival of the fetus." Its effect practically is to downgrade a great
deal of our knowledge of fetal physiology and medicine to anecdotal observation
instead of the genuine research which is vital to completely verified and reli-
able lifesaving information. This is a serious matter, since almost 50 percent
of all biomedical research is funded through NIH.
As a part of this temporary policy, a ban is also laid on keeping fetuses
going ex utero by artificial supports for a few hours (seven or eight at the
most) , even though the fetus is not ultimately viable — in the original sense of
being or becoming able to function independently of the maternal womb. In the
same mood in which they banned the use of artificial support systems to help
fetal life keep going, artificial systems to get life started are also banned —
in the case of in vitro fertilization and implantation. (The 1972 "Peel Report"
of an advisory group on fetal research in Great Britain also asserted, in a some-
what sweeping fashion, that it is "unethical" to do any fetal research in utero
aimed at "ascertaining the harm" drugs and procedures might do.^^ Their ban did
not extend to studies of fetuses ex utero, however; they allowed use of such
fetuses as, simply, "previables. " Their opposition, by the way, was not based
on any assertion of fetal "rights" but on the danger to experimenters of law
suits in torts by disappointed or disgruntled patients.)
But what is of the most urgent importance is that the NIH rules do not dis-
close to those thus regulated any explanation at all of the prohibitions, nor of
the assertion that such research is Unethical. In a civilized, democratic society
it is unthinkable that regulations and prohibitions may be laid upon scientists
and healers in fiat form, without any disclosure or defense of the reasons for
them. Ethically speaking, this is a point of critical significance. Rules with-
out a rationale cut straight across the principle of "due process" and are, as
lawyers like to say, "arbitrary and capricious."
The tension between lifesaving research in genetics, fetology, and general
medicine, on the one hand, and prohibitions of fetal research on the other, is
very real. There is a considerable body of information needed, which is to be
gained only from experiments and investigations with live fetuses in or ex utero;
abortus research does not meet the need. We have to know more about detecting
diseases in pregnant mothers, how to reduce the hazards of induced abortion,
which donor-fetal tissue — thymus, liver, spleen, and so on — will save deficient
newborns (for example, agammaglobulinemia children), and to study abnormalities.
It has been argued (consequentially) that fetal research would have a bru-
talizing effect on us all if it were to be countenanced, but surely the reply is
that it has been done without that effect, before it was brought to a halt; a
more brutalizing effect would be the result of refusing to do what we could to
avert fetal disorders and to avoid bringing disordered babies into the world
knowing that we could prevent such misery. Live fetus research can help to
prevent the 20 to 30 percent of wanted pregnancies lost in spontaneous abortion.
Experiments with maternal/fetal patients whose pregnancies are to be aborted can
achieve impressive gains for life and health. For example, tests of rubella
vaccine by injecting the mothers who consent are necessary, and drugs to know
what sxibstances a fetus can absorb or can cross the placental barrier.
3-7
Fetal experiments ex utero should be done to develop incubator procedures
for prolonging the life of possibly viable premature fetuses, to carry them
along until they can survive enough to enter the nursery; to find treatments
for asphyxiated newborns (e.g., by complete perfusion); to test artificial
placentas to help a newborn with respiratory distress syndrome; to learn about
fetal physiology; to fight birth defects, diagnose disorders, and reduce neo-
natal mortality and morbidity.
Furthermore, research with nonviable live fetuses could lead the way to
therapeutic gains such as thymus for "Swiss type" agammaglobulinemia, donor
transplant tissue, fetal organs for biochemistry, tissue cultures for vaccines,
liver-lung-and-spleen tissue for measles and polio vaccines, and to increase
the accuracy of amniocentesis. The "Peel Report" in Britain listed 51 specific
in utero and ex utero experiments and research goals with live fetuses of impor-
tance to reproduction and general medicine.
The moralistic temper which strives for ever more restrictive antenatal
regulations comes from an ethical stance in which life qua life, regardless of
its quality, is the first order value. Many of us, on the other hand, opt for
quality, not quantity, with the value judgment that sometimes "life is not worth
living." Only if we are "sacralists , " investing life with a sacred entelechy of
some kind, would we want to put a taboo on direct human control over life. We
see this issue underneath both the fetal research debate and the terminal care
debate. The issue runs through nearly all biomedical policy — transplants, deter-
mination of death, triage, and many other problems. Quality or value ethics
requires us to transvaluate our values; we cannot dogmatically put "being alive"
as the highest good. Life is a value to be perceived in relation to other values.
At best it is only primus inter pares. Without life, of course, nothing else is
of any value to us, but — by the same token — without some other things life may
be of no value either.
It is a curious aspect of the consent problem that compulsory motherhood
seems to be a part of the present temporary rules, if the requirement to save a
viable fetus is taken seriously. For example, if a woman's abortion came very
late and the fetus was artificially supported up to viability, it would mean
making her a mother against her will. As it is, in these rules, the patients 's
consent to live fetus research in utero and ex utero is nullified in spite of
her and her physician's hopes and choice.
Dr. Robert Goodlin's work at Stanford on live previable fetuses, including
the product of hysterotomies (one fetus was kept alive for 11 days) was as suc-
cessful as it was because so many patients asked him to do their terminations,
wanting some good to come of their unpleasant experience. The present NIH pro-
hibitions— unreasoned and unexplained — would certainly nullify such compassionate
efforts to help save fetuses born with immature and uninflatable lungs. ^^ This
is a serious invasion of free consent, and especially serious since it is a
policy imposed by those who otherwise make a great parade of respect for consent
as a requirement which should always be enforced.
One of the lurking ethical issues in fetal research is the means-ends con-
troversy. Is risking or damaging fetal life always wrong, an intrinsically evil
act? A categorical moralist might see it that way. Presumably, if fetal life
is personal such acts in research and experimentation would be looked on as
mayhem, battery, or even felonious assault. But looked at hypothetically and
pragmatically, whether doing intended or unintended damage to a fetus is wrong
would depend upon such variables as whether it was to be terminated anyway, or
whether the good to be gained would outweigh the sadness of the means. In a
nondoctrinaire ethics, proportionate good or "a favorable cost-benefit ratio"
would decide it. (For those who do not believe a fetus is a person there is no
question of "murder" or "manslaughter" or "unlawful death" in abortion or fetal
research, but only of choosing to lose or forego a potential person.)
As the editor of The New England Journal of Medicine once expressed it,
to be right "the desired end should always be of sufficient value to justify
the means ..."''* In every responsible profession serving human needs we
have to weigh up the good and bad relatively; ethical analysis is a matter of
choosing between competing alternatives; the moral agent is a chooser in the
clinical or case-focussed spirit, not a straight-down-the-line follower of pre-
fabricated decisional rules. When Dr. Pappworth, as quoted earlier, says that
whether an experiment gains the desired results is "immaterial" to him, because
a "worthy end does not justify unworthy means," we have to part company; his
categorical rigidity is ethically irresponsible.
There are a certain number of people for whom value-tied decision making
is too flexible; they are more comfortable with a rule-tied approach to ethical
problems. Their identity is quickly discoverable because their objection to
letting decision makers judge what is best is never given in the basically doc-
trinaire terms which undergird it but in a variety of objections called the
"slippery slope" or the "thin edge of the wedge." Where there is a trade-off
between protecting fetal life and saving "born" life or learning how to do it,
they complain that a "domino effect" will go into play and that if they are
allowed such medical studies will end up in a reenactment of the "Nazi situation"
or Brave New World or 1984. (The Nazi atrocities perpetrated in the name of
"medical research" were, of course, blatant and ruthless experiments carried out
on involuntary and uninformed subjects.) . .' ,. , ■ . -
This parade of horrors is not logical or rational analysis ethically; it
is a mood objection, not a reasoned one. There is hardly a single advance in
scientific know-how which could not conceivably be turned to stupid and malicious
misuses and abuses. A maxim in the classical tradition of Judeo-Christian ethics
provides an adequate retort to this particular anxiety syndrome. The retort is,
abusus non tollit usum, abuse does not bar use. (There is no "answer" because
there is no analyzable question posed.)
The "fallacy of necessity" lies behind the wedge objection; the notion,
that is, that because we can do something it is certain that we will do it. Or,
more carefully expressed, we will do it uncritically and undiscriminatingly .
Prudence, an ancient and essential virtue, very often turns us against an exper-
iment or research study in fetal medicine because the gain would not be propor-
tionate to the cost — "the flame is not worth the candle." That is prudence.
The wedge objection, on the other hand, as in the case of live fetus research
3-9
or invasive therapy, is imprudent or antiprudent, since it rejects all responsible
ethical judgment with a blanket ban, ab initio. It repudiates critical analysis
in favor of taboo.
ETHICAL JUDGMENTS
Our problem is a political one as much as ethical. How are we to "live
and let live" in American medicine, which functions in a pluralist society com-
posed of varying and even contradictory beliefs and values?
Shall we who are pragmatic and value-oriented compromise with the "pro-
lifers" who are doctrinaire and rule-oriented, or should we follow laissez-
faire? We might put the question in another way: How are we to show our con-
cern and tolerance for minority sentiments, by compromise or by full freedom of
conscience on both sides? Shall we show our acceptance of difference by banning
some categories of live fetus research and allowing others, or should it be not
by "class actions" but by individuating cases — allowing the minority moralists
to choose for themselves in every case whether they will participate or not.
The NIH (DHEW) rules now in effect temporarily have simply meant a capitula-
tion to rule ethics and the prohibitionists — with no explanation or rationale.
Having once controlled society openly, the churches now must try to do so by
tactical political maneuvers — because we have moved in policy making from "Ask
the church" to "Ask society." As psychiatrists concluded in a study about
objection to the abortion as wrong, "we do not believe that their belief should
limit the freedom of those not bound by identical religious convictions ....
General rather thcin specific guidelines should be instituted."'*
Antiresearch elements would probably prefer a compromise, banning some
kinds of experiments if all kinds cannot be stopped. They would not be satis-
fied simply to be honored as committed to one point of view. Their strategy will
be to object to all live fetus research, hoping thereby to get at least a big
part of it eliminated. Their method will be to build consequential and slippery
slope arguments, to support their basically ideological objections. They are
sure to favor completely banning or interdicting whole categories of live fetus
research, rather than to leave the decision whether to participate up to the
individual researcher. Thus many in their school of thought want an amendment
to the Constitution, prohibiting all permissive or voluntary abortion, and all
live fetus research. Since they are not apt to win a success as sweeping as
that, their task will continue to be to harass and minimize live fetal research
as much as possible.
Unhappily but necessarily, if rules are imposed by law or public agencies
somebody is sure to be frustrated; one group or the other. In matters of this
kind there is great wisdom in the old adage, the best government is the least
government. The issue cannot be resolved satisfactorily to all. Ethically
regarded, the minority viewpoint should have to concede, comforted (if at all)
by the reminder that they would not have to engage in any research that violates
their consciences. (One tart suggestion is that we ought to compile a list for
3-10
them of all the drugs and procedures that have and will be derived from live
fetus research, so that they can avoid using them for the protection and health
of their own children. Antifetal research agitators are as inconsistent on this
score as the antivivisectionists. )
The ethical appraisal outlined above takes us to five summary conclusions
about fetal research. Put in terse propositions, they are:
(1) It is justifiable, depending on the clinical situation and the
design, to make any use of abortuses or dead fetuses — whole,
tissues, or uterine materials — whether from voluntary or ther-
apeutic abortions, and with or without maternal consent.
(2) It is justifiable, depending on the clinical situation and the
design, to make any use of live fetuses ex utero, previable or
viable, if survival is not purposed or wanted, and if there is
maternal consent.
(3) It is justifiable, depending on the clinical situation and the
design, to make any use of live fetuses in utero, if survival
is not purposed or wanted, and if there is maternal consent.
(4) It is justifiable, depending on the clinical situation and the
design, to use live fetuses in utero even if survival is
intended, if there is no substantial risk to the fetus, and if
there is both maternal and spouse-paternal consent.
(5) As a fifth finding we may add the point already discussed, that
regulations by the public authority are unethical if the reasons
for them, the ethics they are rested upon, are not disclosed , ■-
fully and frankly.
To say that the best government is the least government does not mean that
government is wholly evil, nor even that it can be called a "necessary evil."
Necessary, yes, but not evil. Fetal research and experimentation should not be
radically individualistic nor a laissez-faire program carried out by personal
whim without any kind of monitoring and control.
The problem is what kind of monitoring and control. Should it be under
institutional peer review and design committees, or governmental? The thrust
of the ethics in this appraisal seems to favor the institutional rather than
the governmental model. Power politics will enter into either structure, but
far less in the institution (a hospital or university medical center, for exam-
ple) than in government politics. It is, therefore, preferable. As Thomas
Jefferson once remarked, the people fear the government in a democracy, and the
government fears the people in an autocracy. For medicine's sake we must pre-
vent any polarization of freedom and responsibility.
It is presumed to be the proper business of legislatures to frame laws
for the greatest good of the greatest number — the aggregate good and the widest
benefit. This ethical question — to whom do we owe our prior obligation, to the
few or the many, the one or the several? — affects live fetus research. Absolut-
izing or tabooing fetal life, even when a fetus is not wanted, is an obvious form
of radical individualism (selfishness and narcissism) , because it would deny the
research use of a live fetus which could provide lifesaving substances for living
persons or yield lifesaving information. We can see this individualism in a past
Pope's claim that the individual may not be subordinated to community needs, as
in medical experiments, because "man [the individual] is not finally ordered to
usefulness to society. On the contrary, the community exists for man [the indi-
vidual ]."i* When related to fetal research a dictum of this kind raises the
issue not only of the general welfare — e.g., perinatal medicine's gains at the
"expense" of an unwanted fetus — but the basic question whether a fetus is a
"man" at all, in any sense.
There is an uncomfortable tension between the individual's interests and
the community's, with authentic claims on both sides, but a balanced ethics
would not finalize the individual (certainly not a fetus) regardless of the cost
to society. Bertrand Russell made this interesting observation: "Christian
ethics is in certain fundamental respects opposed to the scientific ethic ....
Christianity emphasizes the importance of the individual soul, and is not pre-
pared to sanction the sacrifice of one innocent man for the sake of some ulterior
good to the community. Christianity, in a word, is unpolitical, as is natural
since it grew up among men devoid of political power. "i^ In this appraisal, in
any case, a fetus would be held to be expendable if it yielded the medical knowl-
edge wherewith to help many other fetuses, live children, and adults.
Dr. R. H. Moser, editor of The Journal of the American Medical Association,
went to the heart of ethical issues like this one when he advised us succinctly
to decide moral questions according to the case or situation, rather than by
universalizing rules and laying down categorical prohibitions.'^ The wisest
ethical method is situational; nondogmatic, flexible, particularized, value-
oriented. In fetal research, whether with live or lifeless fetuses, what we
are after is the ability to save life and lift its quality. Our goal is useful
medical knowledge.
Two physicians a year or so ago wrote letters to The Journal of the Ameri-
can Medical Association to protest against a previously published paper affirming
fetal research; their complaint was that the writers of the paper had sold out
to "an ethic of expedience" — which they rejected because it "favors utility above
principle. "19 Apparently without realizing it they put their fingers precisely
on the main issue; categorical rules versus weighing pros and cons. If "princi-
ples" block medicine's healing task, so much the worse for such principles.
Medicine must be delivered from the kinds of ethics which follows principles when
following them means we have to condemn and nullify the acquisition of useful
know-how in medicine's effort to save and improve human life.
3-12
REFERENCES
1. Ladimer, I. and Newman, R.W. , "Clinical Investigation in Medicine," Boston:
Boston University Law-Medicine Institute, 1963; Beecher, H.K. , Research
and the Individual: Human Studies, Boston: Little, Brown, 1970, and
Experimentation in Man, Springfield, Illinois: C.C. Thomas, 1959;
Pappworth, H.M. , Human Guinea Pigs, Boston: Beacon Press, 1967; Katz, J.,
Capron, A. and Glass, E.S., Experimentation with Human Beings, New York:
Russell Sage, 1972.
2. Barber, B., Lally, J., Marushka, J., and Sullivan, D. , "Experimenting with
Humans: Problems and Process of Social Control in the Biomedical Research
Community," The Challenge of Life: Biomedical Progress and Human Values,
(Roche Anniversary Symposium), Birkhauer Verlag, Basel and Stuttgart, 1972,
pp. 357-370.
3. Pappworth, M.H. , "Ethical Issues in Experimental Medicine," Updating Life
and Death, Boston: Beacort Press, 1959, pp. 64-84.
4. 410 U. S. 113, 1973.
5. World Medical News, October 5, 1973, p. 36.
6. Ibid.
7. Fletcher, Joseph, The Ethics of Genetic Control, New York: Doubleday /Anchor ,
1974, pp. 91, 137-139.
8. Avery, M.E., "Considerations of the Definition of Viability," New England
Journal of Medicine 292: 206-207, January 23, 1975.
9. Chalkley, D.T., Division of Research Grants, National Instututes of Health,
quoted in Ob-Gyn News 8: 55, April 15, 1973.
10. "Protection of Human Subjects, Policies and Procedures," Federal Register 38:
31738, 1973.
11. "Public Law 93-348," 93rd Congress, H. R. 7724, Sec. 213.
12. Department of Health and Social Security, "The Use of Fetuses and Fetal
Material for Research," London: Her Majesty's Stationery Office, 1972,
p. 6.
13. World Medical News, October 5, 1973, p. 33.
3-13
REFERENCES (Continued)
14. New England Journal of Medicine 269:479, 1962. He was discussing
experiments on children but his reasoning fitted fetal experiments too.
15. Group for the Advancement of Psychiatry, Committee on Psychiatry and Law,
The Right to Abortion: A Psychiatric View, New York: Charles Scribner's
Sons, 1969, pp. 48-49.
16. Pius XII, Acta Apostolicae Sedis 44:779, 784-789, Rome, First Congress
of Neuropathology, 1952.
17. Russell, B., The Scientific Outlook, quoted in J. Katz et al. Experimentation
with Human Beings (see reference 1) .
18. Journal of the American Medical Association 227:432, 1974.
19. Journal of the American Medical Association 230:1124, 1974.
3-14
BALANCING OBLIGATIONS TO THE LIVING HUMAN FETUS
WITH THE NEEDS FOR EXPERIMENTATION
Marc Lappe, Ph.D.
MARC LAPPE, Ph.D.
Dr. Lappe is presently Associate for Biological
Sciences, Institute for Society, Ethics and the
Life Sciences.
PD 304107-5 (15)
Balancing Obligations to the Living Human Fetus
with the Needs for Experimentation
I start from the premise that there are moral "goods" which the nature of
fetal development itself enjoins us to acknowledge. In defending this proposi-
tion, I will be arguing from a "natural law" perspective. The first principle
I derive is that the previable (as well as the viable) human fetus is deserving
of protection from harm and willful neglect in utero; the second, that the
deservedness of the fetus to our protection is an absolute principle, unmodified
by the societal decision to permit abortion during specific periods in pregnancy;
the third, that the facts of the abortion process for a given pregnancy, radi-
cally change the ethical argumentation appropriate for sustaining the protection
of that fetus, and that the circumstances of abortion logically and ethically
make limited experimentation justifiable; fourth, that the "costs" of doing
such experimentation are to be counterbalanced by the goods which are returned
to fetuses as a class so as to as nearly as possible approximate a "therapeutic"
model of experimentation; fifth, that the definition of death of a fetus, an
event which opens many avenues, for potential experimentation, is to be made
independently of the needs of the experimenter. Finally, I will list a series
of policy recommendations which would move towards implementing these principles.
1. The Human Fetus Deserves Protection From Harm In Utero
The nature of the dependency characteristic of intrauterine fetal life —
the fetus's unique vulnerability to environmentally derived and indigenous insult,
its need for certain critical metabolites and anatomical conditions at different
phases in its relationship with its maternal host^ — all give force to the funda-
mental moral charge to respect, protect and nurture the well-being of wanted
fetuses to the fullest possible extent. It is neither the "innocent nature" of
fetal existence, nor its projected "human worth" which move me to this position:
it is the bald evidence derived from the study of perinatology which reveals
that fetuses deprived of the conditions necessary for their normal development
do fail to fulfill their full genetic potential, and if exposed to injurious
substances will be born with handicaps which limit the approximation of their
potential as human persons. In making this argument, I accept the value judg-
ment that it is a fundamental good to ensure, within reason, full expression of
human potential.
I would argue that the other assertions which might militate against this
judgment and its corollary, that the previable human fetus has a claim on us,
are not compelling. For example, one argument that the fetus is exempt from our
moral duty to respect it is that the fetus cannot be regarded as a "moral agent"
because it does not have the capacity to enter reciprocal moral agreements which
4-1
entail rights, claims, duties and obligations. A second argiiment is that the
fetus is not to be granted the status of a "human being." Because it is not yet
human, it lacks the necessary precondition of protection — a recognizable equality
of social worth. The legal view derives from Justice Blackmun's majority deci-
sion in Roe V. Wade that tne previable fetus is not recognized by the law as "a
person in the whole sense" and therefore, the rights of the mother for privacy
in her reproductive decision making override those of the fetus prior to the
acquisition of its full potentiality for independent life.
Reasonable persons may differ as to the proper interpretation of the concept
of "moral agency" or "person"; and legal scholars have contested the Court's
"actual" intent in denying recognition of the fetus's standing. The question of
personhood is clouded by the distinction we might give to "personhood" as an
emergent property defined by the psychobiology of the organism and "personhood"
as a relational property defined by the social nature of persons.^ For example,
Morris-' uses a sociological basis for defining personhood in observing:
"When we talk of not treating a human being as a person or ' showing
no respect for one as a person' what we imply by our words is a
contrast between the manner in which one acceptably responds to
human beings and the manner in which one acceptably responds to
animals and inanimate objects. When we treat a human being merely
as an animal or some inanimate object, our response to the human
being is determined, not by his choices, but ours in disregard of
or with indifference to his." (p. 490)
By this analogy, we might recognize the biological personhood of a fetus,
yet justify responding to it as if it were an animal.
I find this and similar approaches totally unsatisfactory because they are
either untestable (e.g., verifying that the fetus is a "nonperson") ; inconsis-
tent (e.g., the proposition that although the fetus is not a moral agent, it has
some of the rights which we associate with moral agency); or irrelevant (e.g.,
the assertion that the fetus does not have standing in the eyes of the Court
may be taken to pertain only to its claims as they conflict with those of its
mother for privacy, but not to fetal research) .
Where then do I derive the notion that the previable fetus has a legitimate
claim on us for protection? From those socially sanctioned and institutionalized
activities that are universally acknowledged to be desirable and which we already
perform during pregnancy. For example, where we have been able to identify spe-
cific causes of fetal disability during pregnancy (e.g., maternal infection with
rubella or exposure to established teratogens such as thalidomide) , we have
rapidly instituted programs to bring those agents under control. The actions
taken, if scrutinized, will be seen to be directed at preserving fetal and not
necessarily maternal well-being during pregnancy. For example, the idea of mass
vaccination of school age children against rubella to create a "herd" immunity
against a potential pool of contagion is primarily to benefit the fetus, as are
the regulations which now prohibit the prescription of drugs which might be
beneficial to the mother, but of doubtful safety to the fetus. It is well known
4-2
that the Food and Drug Administration has strict policy guidelines which are
scrupulously followed by most, if not all, drug companies which enjoin patients
against the use of a very large proportion of potentially therapeutic agents
during pregnancy (i.e., therapeutic for the mother) for the express purpose of
protecting the previable fetus. ^
The tacit recognition of the needs of the fetus give substance to the claim
that we already behave towards previable fetuses (as distinct from their mothers)
as if they were deserving of protection. We can test, along with moral philoso-
pher R. M. Hare, the measure of our obligation by asking ourselves how we would
wish others to have behaved toward us. The answer is straightforward and unam-
biguous: We consider ourselves deserving of such protection because we would
wish others like us to have received the same protection. ("Others like us,"
however, does not include those potential human beings whose existence has been
terminated through abortion.)
2. The Deservedness of the Fetus to Protection Is not Altered by Societal
Acquiescence to the Need for Abortion
As I understand it, the decision to allow a woman, in conjunction with a
medical practitioner, to remove a previable fetus from her body for whatever
personal reasons so motivate her was based on a balancing of constitutional
claims of the fetus to its emergent potentiality for independent existence
against those of the mother for privacy in her reproductive decision making.
Simply because the Court made a decision which allowed a woman to make th^
autonomous decision that a fetus will no longer receive her protection, it does
not follow that others in society are similarly enjoined. The fetus, theoret-
ically, still retains those other nebulous "rights" which the Court alluded to
in allowing that during the second trimester states may assert their interest
in potential life beyond the protection of the pregnant woman. Unfortunately,
the Court offered no guidance as to what constituted proper medical conduct in
removing the fetus from the mother- -and more importantly, how the fetus was to
be treated once out of the womb.
Because some of the abortions performed late in the second trimester will
necessarily bring some fetuses close to the established point for viability,^
many fetuses have been aborted alive (witness the recent Edelin case) . Once
out of the womb, these fetuses have claims on our duties to afford them protec-
tion from experimentation by virtue of our basic medical tenets to preserve
life. However, the procedures we can institute to protect potentially viable
fetuses ex utero depends in part on how carefully we have considered the method-
ologies used to abort them.
Space will not allow a complete treatment of the full range of techniques
which are being developed to permit abortions to be done with relatively low
risks of maternal morbidity and mortality. The most commonly used mid-trimester
technique through the early 1970s, saline abortion, underscores part of the
dilemma. The concentrated salt solution which indirectly induces cervical
dilation (laminaria tents may be used) and uterine contractions, was originally
4-3
chosen because of its relatively low incidence of maternal morbidity. The fetus,
however, is apparently exposed to severe damage, including salt poisoning and
intravascular clotting.
Considering fetal experimentation in this context illustrates the cross-
purposes at which we now find ourselves. By the choice of abortion techniques
which completely disregard the potential physiological needs of the fetus, we
utilize procedures which may so damage the fetus as to preclude meaningful
debate on restoring conditions ex utero which would permit continued normal
development.
As long as the objective of a pregnancy was generally recognized to be the
delivery of a live, nutritionally sound, physically intact (i.e., a "healthy")
fetus, experimentation during the prepartum period was firmly bound to the
Hippocratic tradition of sustaining life and primum non nocere (above all else,
do no harm) . We were constrained to limit any intrusive or potentially harmful
experimentation in keeping with the principles which guided experimentation on
other nonconsentual persons whose well-being we had at heart. It is logical
that once that constraint was abridged for the purposes of the radical experi-
ment of abortion, the ethical obligations owed to that class of persons poten-
tially subject to minor experimentation become less tenable. I believe that
the abortion decision, while not related to the general charge to respect the
rights of fetuses to protection, does condition the debate concerning those
individual fetuses which are themselves subject to abortion.
3 . The Conditions Under Which We Respect the Fetus's Right to Protection
are Compromised by the Decision and Actions Taken to Abort It
In a purely physical sense, the technique we elect to perform that abortion,
itself selected on the basis of maternal and not fetal considerations, delimits
the range of moral concern which we may logically continue to show to the fetus
once it is aborted. I cannot accept the view, morally sound as it may be, that
we must continue to treat the abortus as if it were a potential human life.
In an ideal world, perfect moral scrupulosity would protect the fetus
throughout its gestation — and all fetuses would be born intact and wanted. There
is a moral consistency to those who would deny both the acceptability of abortion
and the permissability of research on the fetus. At the same time, it is morally
inconsistent to accept our "right" to destroy the fetus but to reject any case
which might be made to utilize that death for humanitarian purposes. The incon-
sistency stems from the failure to balance concern for the severity of abortion
techniques and utter disregard of the fetus in effecting its abortion against
concern for protecting the fetus from abuse after it is aborted.
A middle ground, one which I advocate, is to include in the guidelines for
fetal experimentation controls over the nature of experimental abortifacient
research, such that the development and utilization of new technologies which
subject the fetus in utero to "extreme violence" or other grossly unacceptable
procedures may be controlled. Moral concern for the fetus would dictate the
choice of procedures which not only subjected the mother to small risks of mor-
bidity, but would expeditiously expel the previable fetus — and ideally, simul-
taneously render it incapable of extrauterine survival. Thus, the purportedly
elective choice to defer abortion in patients at 13-15 weeks gestation for abor-
tion by intra-amniotic saline at 16 weeks or later not only poses greater risks
of morbidity to the mother,^ but also places at risk a potentially sensate fetus
(ganglia extend fibers into body organs and skin, and the spinal cord and brain
form their first connections around 20-22 weeks of gestation) which previously
(at 13-15 weeks) did not likely have the biological basis for perceiving pain.
The development and use of prostaglandins is apparently unregulated by the
temporary ban of fetal research (see reference 7, for example). Such research
poses extreme ethical problems for fetal experimentation (even though the
intended subject is the mother) because of the increased likelihood of "natural"
patterns of labor which pose less likelihood of fetal distress and intrapartum
death, and therefore result in the birth of more living previable fetuses than
accomplished by previous techniques. Concern for the treatment of these fetuses
postabortion (abortuses) should be evinced by this committee's recommendations.
To reemphasize a critical point: The fact that we allow the abridgment of
the rights of the fetus for some purposes (e.g., respecting the claims of the
mother for privacy in reproductive decision making) does not dictate the abridg-
ment of our responsibility for other protective acts towards the fetus. In this,
I am in agreement with the original NIH policy proposal on fetal research that
"the decision of the Supreme 'Court on abortion does not eliminate the ethical
issues involved in research on the nonviable human fetus."* However, once we
have incurred the costs of doing abortion, the moral universe in which we have
to operate is in fact changed, and we acquire new moral duties. One of those
new duties is to act in ways which prevent mass abortion from eroding our moral
sensibility to wanted fetuses and newborns; another is to rectify the costs of
doing abortion by ethical behavior, both in the manner in which abortions are
done, and in the uses to which aborted fetuses are put.
4. Balance the Costs of Doing Fetal Research With the Resultant Goods
The fine line to be drawn in any attempt to redress the balance of moral
goods and wrongs in fetal research is to ensure that the proposed solutions do
not add to any moral wrong which has already been committed.
Paul Ramsey has addressed this dilemma at length in his book on fetal
research. ^ Where there is a question of medical experimentation on a fetus pre-
or postabortion, the "fact" of abortion forces us to examine two conflicting
moral choices. We may either resist, in Paul Ramsey's words, the temptation
"to wrest some good out of guilt-laden harmfulness to unborn life" (his view of
abortion); or we may, in Willard Gaylin's and my own view, "endow the process
of abortion with human values it would not otherwise have had.^°
When Gaylin and I make the case for intrauterine research on a still-living
human fetus, ^° we do so on the basis of an ethical calculus which balances
4-5
the moral harm of acting against the moral harm of not acting (not only the
accrued good of those acts). For example, we justify preabortion in utero
research of attenuated viral vaccines intended to protect the fetus against
congenital malformation or death by citing the good of minimizing the potential
harm done to a larger population of fetuses which are at risk for defect, and
the moral weight of having to consider abortion for additional wanted fetuses.
It is an oversimplification to state that we have appended a lesser moral wrong
to a greater one (as Ramsey insists) . What we have done is add a moral good
to a morally tragic situation. We would not, for example, want to justify addi-
tional abortion-related research which did not have the intention of aiding
fetuses, but neither would we have our "good" case justify more abortions to
give more subjects for research.
Abortion should not be construed to give license to any and all experimen-
tation (and here I agree with Ramsey) . The fact of imminent demise does not
provide a sufficient rationale for experimentation on the still-living fetus.
The ethical rationale for research involving the living fetus preabortion must
include a consideration of potential harm and risks to the fetus and mother, but
the determination that the procedure is risk- free, as it would were it to be
in the ethical domain of acceptable experimentation for nontherapeutic purposes
on nonconsentual persons, need not be made. (Recall that I have not based my
argumentation on the unascertainable fact that the fetus is a "person," but
rather on our collective understanding of the different duties we owe the fetus
as a potential person.)
A minimum of two conditions would seem to be required for any preabortion
experimentation. The legitimate purposes of the experimentation must be estab-
lished, and defined within a methodology that does not offend our moral standards.
And, secondly, the mother must retain the right to refuse to allow herself (and
her fetus) to be experimented upon.
Assuming for the moment the validity of the research procedure, the problem
of consent is one that gives us most difficulty. Even were the fetus accorded
the rights of personhood, it would obviously not be capable of granting its own
consent, and it is problematic to do as in other conditions where an individual
is deemed incompetent to stand for himself, and delegate a proxy. In the cases
of a child, the parent is the usual proxy. But in the case of the fetus-to-be-
aborted, the parent cannot be said to have the interests of the fetus at heart.
Even here there are limitations, depending on the nature of the experiment.
Roughly speaking, experimentation can be divided into two classes: The first is
experimentation to perfect or develop as yet unproven therapies which involve
using a drug or procedure before it has been adequately proved out on an indivi-
dual often as a last desperate measure in the treatment of a condition which is
threatening to life. The purpose of such research may be to help the siibject
as well as to do research or it may be a complex mixture of an intent to aid
with the need to perfect the therapy such that it will be more efficacious next
time.
The second category may be thought of as philanthropic. The subject offers
himself for humanitarian purposes to be the subject of an experiment which may
4-6
harm him and which serves no personal selfish interests. Many of us have felt
that, with rare exceptions, no nontherapeutic form of philanthropic experimen-
tation may be permitted on a proxy basis. I have assumed that while it is a
noble thing to offer oneself to science it is somewha>; less generous to sacrifice
someone else. Were the fetus regarded as worthy of all the rights of personhood,
it would fall into this classification, and be immune from nontherapeutic experi-
mentation. But were the fetus so regarded, we would not be free to take its
life, and indeed there lies much of the covert opposition to this research.
That group which cannot reconcile itself to the Supreme Court decision (and
therefore the law of the land) will logically oppose any activity that builds on
the right to abortion even if (particularly if) it allows the abortion to contri-
bute to some common good. They do not want to risk the legitimation of what they
consider "legalized murder."
In establishing a minimal case for experimentation on the living fetus, we
should first eliminate all research which could just as well be done on labora-
tory animals as on the fetus. Unfortunately, this is all too common in current
practice. The fetus must never be seen as a convenient or inexpensive laboratory
animal. The insensitivity of certain researchers in conducting precisely such
experimentation has been responsible for generating much revulsion in the field.
Secondly, we would draw an arbitrary line between in utero and ex utero research,
recognizing that a whole set of new considerations and new moral dilemmas are
created when we extend the life of a fetus outside of the womb for purposes of
experimentation. And thirdly, we would distinguish research done on the expend-
able or replenishable by-products of conception, notably those cells shed into
the amniotic fluid, or the fluid itself, recognizing that contingent upon ade-
quate demonstration of the safety of obtaining these materials through "amniocen-
tesis," this research raises special problems other than violating the integrity
of the fetus.
The most justifiable experiment would seem to us to be that which is closest
to the therapeutic model. Of course, in the abortion model it cannot help the
fetus to be experimented upon since it is doomed to death anyhow, but perhaps
it can ennoble that death by utilizing it to serve its more, fortunate fellows,
i.e., a research designed to help in preserving the life, health or integrity
of untold wanted children. If the doomed fetus could be utilized to supply the
information that could permit those same parents, or similar parents, a greater
opportunity for a healthy, wanted child it would be a persuasive argument for
experimentation. The classic example would involve: a disease which is lethal
or damaging to the gestating child; a vaccine or drug which would prevent the
disease in an expectant mother; the vaccine has been proved harmless or the drug
efficacious to adults; its effect on the developing fetus is unknown, i.e., it
may be harmless, or therapeutic, or it may be more destructive than the disease.
5. The Definition of Death of a Fetus, Which Is the Potential Subject of
Experimentation Is to be Made Independently From Any Eventual Use
I recognize that the question of when it may be acceptable to perform cer-
tain types of fetal experimentation will be contingent upon whether or not it
4-7
has been possible to determine incontrovertibly that the fetus is in fact "dead."
The definition of "death" presupposes that one understands the distinction
between "alive" and "dead" in physiological terms, and more important, that one
understands what it is that "dies."
A fetus (from the Aryan root, bheu meaning to become) is distinguished from
the child, or adult, by virtue of the fact that its "living" is simultaneously a
"becoming": It is defined in terms of what it will be as well as what it now is.
Death for a fetus or an embryo may be physiologically distinct from death
for a child, since, for example, embryonic and fetal tissues have a much higher
tolerance to anoxia (reduced oxygen levels) than do those of the infant. When
a fetus dies is further complicated by the question of when it becomes meaning-
fully alive. It is one thing to speak of "the death of a person," but another
to spealt of the death of something which is not yet a person.
For example, the body of a human being is not a person. Even when, by the
brain definition of death, a body has a pulsing heart, an active endocrine system,
a functioning hematopoietic system, and respiratory exchange, it is nonetheless
no longer a person. It is therefore subject to the kind of experimentation,
dissection, exploitation and abuse that we do not allow to a living person.
This, in part, is why the question of personhood appears to be crucial in any
treatment of the fetus — if we wish to argue symetrically we would be forced to
ask if the fetus is to be denied personhood until cortical activity starts, or
only after it achieves the capability of some semblance of human interaction.
But as I have stressed, such reasoning is inherently suspect; a person — potential
or real — cannot be measured by biology alone any more than it can by religious
standards.
The ethical considerations for determining that a potential human organism
is in fact no longer alive include at least the following:
A. That the criteria chosen should be completely independent of
the ultimate uses to which that organism is to be put, if any;
and
B. That the deliberations and conclusions used to decide upon
the time of death of a fetus should not be influenced by the
ultimate research needs.
These positions, as enumerated in a report from the Task Force on Death and
Dying at the Hastings Institute, included the arguments that the choice of cri-
teria for pronouncing a person dead, as well as the procedures, criteria and the
actual judgment in determining the death of that one human being, should "not be
contaminated with the needs of others, no matter how legitimate those needs may
be."^' Therefore, according to the signatories, it is ethically imperative to
have a universally agreed-upon test for determining that death has occurred.
To summarize our previous recommendations as they would apply to the fetus :
(1) the criteria should be unambiguous and involve assessment of the presence
or absence of recognized indicators of aliveness, e.g., heartbeat; (2) the tests
should be simple, such that they can be done easily and conveniently by nurses
or physicians of ordinary competence; (3) the test should include a measure of
the permanence of loss of any vital functions; (4) more than one function should
be included among the criteria. (My own recommendations follow from here) :
(5) the attempt to ascertain absence of cortical activity need not be made in
the case of the fetus; (6) attempts to ascertain the presence or absence of vital
signs in an aborted fetus should not themselves be resuscitative; (7) in the
absence of spontaneous signs of life, no resuscitation should be attempted.
POLICY RECOMMENDATIONS " ' ." "
1. That the committee affirm its commitment to protect fetuses while in utero
from injury, willful neglect, or undue harm.
2. That such statement be made morally congruent with the general need for such
regard during pregnancy, so as to include concern for classes of abuse or
neglect that are outside the experimental model, including:
• Controllable maternal exposure to potentially injurious agents
• Choice of abortifacients .
3. That the committee permit only very limited research on viable fetuses in
utero which are subjects of abortion, such research to be guided by the
following principles:
• That nontherapeutic experimentation is permissible where it .
involves no risk of harm or defect or no increase in risk to
the subject in its immediate preabortion state
• That the objective of the experiment be to obtain knowledge
which affords fetuses as a class protection from potentially
life-threatening or defect-producing agents.
4. That research intended to benefit society generally or other basic studies
be performed on the previable fetus after ascertaining that it has died.
5. That the ascertainment of death be made by criteria which separate the pur-
poses of experimentation from either the technique chosen for abortion, or
the methodology for ascertaining that death has occurred.
4-9
REFERENCES
1. An unpublished review on the nature of the dependency characteristic of the
fetal/maternal relationship was previously transmitted to the Commission.
2. The newborn, for example, would be given such standing because it rapidly
undergoes a mutual process of socialization with its mother which appears
to be a necessary concomitant to its orderly neurological, psychological
and physical development.
3. Morris, Herbert, "Persons and Punishment," The Monist 52: 475-501, 1968.
4. In part because the teratological susceptibility of the organ systems of
the implanted, developing embryo is concentrated in time windows early
in pregnancy for all but the central nervous system, it makes no biologi-
cal sense to make policy recommendations for protecting fetuses against
potential abuse in or out of experimental settings along a sliding scale
of viability, increasing the protective covenants as the fetus reaches
independent existence. This view, of course, also assumes that the objec-
tive of the pregnancy in question is to bring the fetus to term. However,
it is underscored by the fact that newer techniques of abortion are com-
parably safe in the first and second trimester (Cf. I.Z. Mackenzie et al,
"Prostaglandin-Induced Abortion: Assessment of Operative Complications
and Early Morbidity," British Medical Journal 2:683-686, 1974.)
5. Dr. Skylar Kohl reported at the Edelin trial that of 121,264 births which
he compiled between 1961 and 1972 , six out of 283 babies born who weighed
700-799 grams at birth survived; this weight corresponds to a gestational
age of about 20-21 weeks.
6. Brenner, W.E. and Edelman, D.A. , "Dilatation and Evacuation at 13 to 15
Week's Gestation Versus Intra-Amniotic Saline After 15 Weeks Gestation,"
Prostaglandins 1 : 1710180, 1974.
7. Schulman, H. , et al, "Prostaglandin E2 Induced Abortion With Vaginal Supposi-
tories in a Contraceptive Diaphragm," Prostaglandins 1 : 195-205, 1974.
(This work was submitted after the ban on fetal research took place in
early July 1974.)
8. federal Register 38 (No. 221), November 16, 1973.
9. Ramsey, P., The Ethics of Fetal Research, New Haven: Yale University Press,
1975, pp. 31-50.
10. Gaylin, W. and Lappe , M. , "Fetal Politics," Atlantic Monthly, May 1975.
11. Task Force on Death and Dying of the Institute of Society, Ethics and the
Life Sciences, "Refinements in Criteria for the Determination of Death:
An Appraisal," Journal of the American Medical Association 221:48-53, 1972.
To summarize our previous recommendations as they would apply to the fetus:
(1) the criteria should be unambiguous and involve assessment of the presence
or absence of recognized indicators of aliveness, e.g., heartbeat; (2) the tests
should be simple, such that they can be done easily and conveniently by nurses
or physicians of ordinary competence; (3) the test should include a measure of
the permanence of loss of any vital functions; (4) more than one function should
be included among the criteria. (My own recommendations follow from here) :
(5) the attempt to ascertain absence of cortical activity need not be made in
the case of the fetus; (6) attempts to ascertain the presence or absence of vital
signs in an aborted fetus should not themselves be resuscitative; (7) in the
absence of spontaneous signs of life, no resuscitation should be attempted.
POLICY RECOMMENDATIONS
1. That the committee affirm its commitment to protect fetuses while in utero
from injury, willful neglect, or undue harm.
2. That such statement be made morally congruent with the general need for such
regard during pregnancy, so as to include concern for classes of abuse or
neglect that are outside the experimental model, including:
• Controllable maternal exposure to potentially injurious agents
• Choice of abortifaciehts .
3. That the committee permit only very limited research on viable fetuses in
utero which are subjects of abortion, such research to be guided by the
following principles:
• That nontherapeutic experimentation is permissible where it ■■:. ■■"■■■
involves no risk of harm or defect or no increase in risk to '. ..
the subject in its immediate preabortion state , ...
• That the objective of the experiment be to obtain knowledge
which affords fetuses as a class protection from potentially -; ;■ .
life-threatening or defect-producing agents.
4. That research intended to benefit society generally or other basic studies
be performed on the previable fetus after ascertaining that it has died.
5. That the ascertainment of death be made by criteria which separate the pur-
poses of experimentation from either the technique chosen for abortion, or
the methodology for ascertaining that death has occurred.
4-9
REFERENCES
1. An unpublished review on the nature of the dependency characteristic of the
fetal/maternal relationship was previously transmitted to the Commission.
2. The newborn, for example, would be given such standing because it rapidly
undergoes a mutual process of socialization with its mother which appears
to be a necessary concomitant to its orderly neurological, psychological
and physical development.
3. Morris, Herbert, "Persons and Punishment," The Monist 52: 475-501, 1968.
4. In part because the teratological susceptibility of the organ systems of
the implanted, developing embryo is concentrated in time windows early
in pregnancy for all but the central nervous system, it makes no biologi-
cal sense to make policy recommendations for protecting fetuses against
potential abuse in or out of experimental settings along a sliding scale
of viability, increasing the protective covenants as the fetus reaches
independent existence. This view, of course, also assumes that the objec-
tive of the pregnancy in question is to bring the fetus to term. However,
it is underscored by the fact that newer techniques of abortion are com-
parably safe in the first and second trimester (Of. I.Z. Mackenzie et al,
"Prostaglandin-Induced Abortion: Assessment of Operative Complications
and Early Morbidity," British Medical Journal 2:683-686, 1974.)
5. Dr. Skylar Kohl reported at the Edelin trial that of 121,264 births which
he compiled between 1961 and 1972 , six out of 283 babies born who weighed
700-799 grams at birth survived; this weight corresponds to a gestational
age of about 20-21 weeks.
5. Brenner, W.E. and Edelman, D.A. , "Dilatation and Evacuation at 13 to 15
Week's Gestation Versus Intra-Amniotic Saline After 15 Weeks Gestation,"
Prostaglandins 1 : 1710180, 1974.
7. Schulman, H., et al, "Prostaglandin E2 Induced Abortion With Vaginal Supposi-
tories in a Contraceptive Diaphragm," Prostaglandins 7: 195-205, 1974.
(This work was submitted after the ban on fetal research took place in
early July 1974. )
8. Federal Register 38 (No. 221), November 16, 1973.
9. Ramsey, P., The Ethics of Fetal Research, New Haven: Yale University Press,
1975, pp. 31-50.
10. Gaylin, W. and Lappe , M. , "Fetal Politics," Atlantic Monthly, May 1975.
11. Task Force on Death and Dying of the Institute of Society, Ethics and the
Life Sciences, "Refinements in Criteria for the Determination of Death:
An Appraisal," Journal of the American Medical Association 221:48-53, 1972.
4-10
EXPERIMENTATION ON THE FETUS:
POLICY PROPOSALS
Richard A. McCormick, S.J.
RICHARD A. Mccormick, s.j.
Dr. McCormick is presently Professor of Christian
Ethics, Kennedy Institute, Georgetown University.
PD 304214-5 (15)
Experimentation on the Fetus:
Policy Proposals
1. DEFINITION OF TERMS
By the term "experimentation" as used here, I understand all procedures
not directly beneficial to the subject involved. (There is little moral prob-
lem and should be little policy problem where procedures are experimental but
represent the most hopeful therapy for an individual.) By the term "nonviable
fetus" I understand a fetus incapable of extrauterine survival. (Attention in
this study will be restricted to the nonviable fetus because I shall suppose
that in all decisively relevant moral and policy respects touching experimen-
tation, the viable fetus should be treated as a child.) The nonviable fetus,
as an experimental subject, could be further subdivided as follows:
In Utero Extra Uterum
No abortion contemplated - Spontaneous abortion
Tvv, 4. ■ 1 ' J ~ living
Abortion planned ,
^ ,- ^ ■ ~ dead
- prior to abortion
- during abortion - Induced abortion*
- after abortion* - living
- living - dead
- dead
(*Probably identical in all decisive respects)
2. MORALITY AND PUBLIC POLICY
Before sound public policy proposals can be developed, the relationship
between public policy and morality must be clarified. Morality concerns itself
with the Tightness or wrongness of our conduct. Law or public policy, on the
other hand, is concerned with the common good. Clearly, then, morality and
public policy are both related and distinct. They are related because law or
public policy has an inherently moral character due to its rootage in existential
human ends (goods). That is, the common good of all persons cannot be unrelated
to what is judged to be promotive or destructive to the individual (sc, moral
or immoral) . They are distinct because it is only when individual acts have
ascertainable public consequences on the maintenance and stability of society
that they are the proper concern of society, fit subjects for public policy.
Once this point has been made, several additional clarifications are in
order. First, what actions ought to be controlled by policy is determined not
5-1
merely by the immorality of the action, but beyond this by a single criterion:
feasibility. Feasibility is "that quality whereby a proposed course of action
is not merely possible but practicable, adaptable, depending on the circumstances,
cultural ways, attitudes, traditions of a people . . ."^ Feasibility, therefore,
looks to questions such as: Will the policy be obeyed? Is it enforceable? Is
it prudent to undertake this or that ban in view of possibly harmful effects in
other sectors of social life? Can control be achieved short of coercive measures?
And so on. The answer to the feasibility test depends on the temperature of a
society at any given moment in its history.
I make this point in discussing fetal experimentation because the feasi-
bility test is particularly difficult in our society and will profoundly affect
the Commission's policy proposals. Ultimately public policy must find a basis
in the deepest moral perceptions of the majority or, if not, at least in prin-
ciples the majority is reluctant to modify. ^ This means that it is especially
difficult to apply the feasibility test where fetal experiments are concerned,
for the good itself whose legal possibility is under discussion is an object of
doubt and controversy. That is, the moral assessment of fetal life and value
differs.
A second point to be made is that policy will not infrequently go beyond
morality. Concretely, while one might morally justify this or that experimental
procedure on the fetus , the danger of abuse or miscalculation might be so con-
siderable as to call for a policy ban, or safe-side regulatory cautions. It is
one thing, for instance, to justify morally a single sterilization on a mentally
retarded girl in her own best interests. However, when one sees five years later
that his moral reasoning has been used to sterilize 100,000 indigent blacks, then
an exceptionless policy may be called for, or at least safe-side regulations to
prevent such abuse.
3. MORALITY AND FETAL EXPERIMENTATION
The literature on this subject (to be reported below) is very sparse.^
What does exist has drawn attention to the analogies with experiments on children.
However, at least two things must be noted about this analogy. First, whether
the question of fetal experimentation approximates, and indeed, is in most crucial
respects identical with experimentation on children, depends on one's assessment
of fetal life. If one regards the fetus as "disposable maternal tissue" or as
"potential human life" only, then the questions are sharply different and will
yield a different moral conclusion, and ultimately a different public policy.
If, however, the nonviable fetus is viewed as "protectable humanity" or a "person"
with rights, then the problems are quite similar. Secondly, the nonviable fetus
(whether abortion is contemplated or not) is in a dependency relationship, its
health and growth being linked more or less to maternal health. This relation-
ship can be read in a variety of ways in terms of its ethical yield. But one
thing all would agree on is that whatever fetal experimentation is judged to be
warranted, it must take account of maternal health.
Thus while there are possible differences in these two problems (experi-
ments on children and fetuses), there are important continuities. If one judges
all experimentation on living children (even if they are dying) to be an abuse
and iiranoral and at the same time regards the nonviable fetus as a person in his
own right (even though within a dependency symbiosis) , it is safe to say that he
will condemn (morally) all experimentation on living fetuses in whatsoever con-
dition they be. Contrarily, if one morally justifies some experimentation on
children, it is quite possible, though not inevitable, that he could and would
extend this justification to fetuses.
There are two identifiable schools of (moral) thought where experimentation
on children is concerned. The first is associated with Paul Ramsey "* and is
supported by William May.^ The second is the position of Curran,^ O'Donnell'
and McCormick.^ Ramsey argues that we may not submit a child to procedures that
involve any risk of harm or to procedures that involve no harm but simply
"offensive touching." A subject can be wronged without being harmed. This
occurs whenever he is used as an object, or as a means only rather than also as
an end in himself. Why is this so? Ramsey argues as follows: "To attempt to
consent for a child to be made an experimental subject is to treat a child as
not a child. It is to treat him as if he were an adult person who has consented
to become a joint adventurer in the common cause of medical research. If the
grounds for this are alleged to be the presumptive or implied consent of the
child, that must simply be characterized as a violent and false presiomption. "
Therefore Ramsey concludes that no parent is morally competent to consent that
his child be submitted to any nontherapeutic experimentation.
Thomas O'Donnell accepts the moral validity of vicarious consent where the
"danger is so remote and discomfort so minimal that a normal and informed indi-
vidual would be presupposed to give ready consent."^ Charles Curran has drawn
a similar conclusion, but without supporting moral reasoning. He states: "I
would maintain that children can be used in experimentation if there is no
discernible risk to them, and their parents consent. "i°
I have attempted to argue for a position that would allow experimentation
on children where there is no discernible risk or undue discomfort. ^^ The
position departs from Ramsey practically only if he disallows any give and play
with the term "discernible risk." More importantly, it is at one with Ramsey's
analysis in rejecting any utilitarian evaluation of children's lives that would
submit their integrity to a quantity-of-benef its calculus far beyond any legit-
imately constructed consent. The heart of my argument is this: if we analyze
proxy consent where it is accepted as legitimate (sc, in the therapeutic
situation) we will see that parental consent is morally legitimate because, life
and health being goods for the child, he would choose them because he ought to
choose the good of life. In other words, proxy consent is morally valid pre-
cisely in so far as it is a reasonable presumption of the child's wishes, a
construction of what the child would wish could he do so. The child would so
choose because he ought to do so, life and health being goods definitive of
his flourishing.
Once proxy consent in the therapeutic situation is analyzed in this way,
the question occurs: Are there other things that the child ought, as a human
being, to choose precisely because and in so far as they are goods definitive
of his well-being? As an answer to this question I have suggested that there
5-3
are things we ought to do for others simply because we are members of the human
community. These are not precisely works of charity or supererogation (beyond
what is required of all of us) but our personal bearing of our share that all
may prosper. They involve no discernible risk, discomfort or inconvenience yet
promise genuine hope for general benefit. In summary, if it can be argued that
it is good for all of us to share in these experiments, and hence that we ought
to do so (social justice) , then a presiimption of consent where children are
involved is reasonable and proxy consent becomes legitimate.
The moral reasoning outlined above yields a conclusion that is shared, at
a practical level, by Curran,* Beecher,i2 Ingelf inger , i^ the Helsinki Declara-
tion,^'* the Archives of Disease in Childhood ^^ and others. Yet it has built
into it rational limits and controls not always present in merely practical
statements.
With this as a background we now turn to fetal experimentation itself.
What one judges to be morally appropriate and acceptable where fetal experiments
are concerned depends above all on his evaluation of the fetus. Here there are
two general schools of thought. The first would regard the fetus as a nonperson
or as "potential human life." These terms are used in the moral, not the legal
sense, though it is clear that one who is not a person morally should not be
considered such legally. At any rate, one who is not a moral person, who is
morally a nonperson — and therefore not the sxibject of rights and claims — seems
to present little problem where experimentation is concerned. One who holds
this position ought to conclude, if his moral reasoning is consistent, that
experimentation on the fetus is legitimate and desirable, or if there are to be
restrictions they are rooted in values other than the fetus itself in its present
state.
The second general school of thought is that the fetus is, indeed, pro-
tectable humanity, and an appropriate subject of rights. Within this school of
thought, three distinct tendencies or siibdi visions are identifiable: (1) The
fetus is protectable humanity but to be valued less than a viable fetus or born
infant. This school would probably tolerate experiments if the benefits are
great, but no literature has made this conclusion explicit. (2) The fetus is a
fellow human being and must be treated, where experimentation is concerned,
exactly as one treats the child. Just as the child may not be exposed not only
to harm and risk, but also to "offensive touching," so the fetus may not be
exposed to any risk or even to "offensive touching." This would seem to be the
position of Ramsey.'® Concretely, at one point the nonviable fetus is to be
likened to an unconscious patient; at another point the nonviable living fetus
(after instances of spontaneous or induced abortion) is to be likened to a
dying patient; prior to an induced abortion the fetus is to be likened to the
condemned. Since it is immoral to experiment on the unconscious, and, without
their consent, on the condemned or dying, it is immoral to experiment on the
fetus — and this would apply even to "offensive touching." In logic Ramsey ought
to conclude that no experimentation on living fetuses is morally warranted.
(3) The fetus is a fellow human being and ought to be treated, where experimen-
tation is concerned, exactly as one treats the child. However, experiments on
children, where no discernible risk or discomfort is involved, is morally legi-
timate if appropriate consent is obtained and if the experiments are genuinely
necessary (trials on animals are insufficient) for medical knowledge calculated
5-4
to be of notable benefit to fetuses or children in general. This is an extension
to the fetus of the moderate position on children outlined above. It is, I
believe, a defensible moral position — but the way the position is defended is
utterly crucial (I shall return to this below) if sufficient protection of human
subjects is to be assured.
The position just outlined is the one I would attempt to defend and the
one I would propose to the Commission as the basis for its policy proposals.
But since the fetus can be in a variety of postures or situations, this general
approach must be carefully applied to this variety of postures. I emphasize
here that I am discussing for the present a moral position (not immediately
what public policy ought to be) and one that reflects my own views.
For purposes of clarity and precision, the original outline under defini-
tion of terms will be followed.
A. The Fetus In Utero
(1) No Abortion Contemplated. Theoretically, if there is no dis-
cernible risk or discomfort to the fetus and to the mother, and appropriate
proxy consent is obtained, such experimentation could be defended as morally
legitimate--on the same grounds that identical experiments on children could be
defended. Practically, however, one must question the necessity of experimenta-
tion here (a factual matter). If fetal material is otherwise available, experi-
mentation here would be .inappropriate precisely as unnecessary.
(2) Abortion Planned. Here a preliminary general reflection is in
order. It applies to the fetus prior to abortion, during abortion, and after
abortion (whether the fetus be living or dead) . It is the issue of cooperation.
If one objects to most abortions being performed in our society as immoral, is
it morally proper to derive experimental profit from the products of such an
abortion system? Is the progress achieved through such experimentation not
likely to blunt the sensitivities of Americans to the immorality (injustice) of
the procedure that made such advance possible, and thereby entrench attitudes
injurious and unjust to nascent life? This is, in my judgment, a serious moral
objection to experimentation on the products of most induced abortions (whether
the fetus be living or dead, prior to abortion or postabortional) . It is
especially relevant in a society where abortion is widely done and legally pro-
tected.
However, I have no confidence that a society that does not share the under-
lying judgment on most abortions and is so highly pragmatic as to be insensitive
to the issue of cooperation will be impressed by this moral consideration — factors
that must be taken into account where public policy (feasibility) is concerned.
That is, public policy must root in the deepest moral perceptions of the majority,
or at least, in principles the majority is reluctant to modify. Since there is
such profound division on the moral propriety of abortion, the moral notion of
cooperation in an abortion system will not function at the level of policy.
5-5
(a) Prior to Abortion. One cannot approach the position of the
fetus without a further distinction. If the planned abortion is morally legi-
timate, we might say that the fetus is in the situation of the tragically but
justly condemned individual. In this instance, if the proposed experimentation
will involve no discernible risk to the fetus, I believe that proxy consent
(of the mother) would be a defensible construction of fetal wishes. If, however,
the proposed experimentation will involve discernible risks to the fetus, then
proxy consent is an invalid construction. If the planned abortion is not morally
legitimate, we might say that the fetus is in the situation of an unjustly con-
demned individual. In my judgment, this is the case with most abortions now
being planned and performed. In this instance, the full moral weight of the
cooperation issue strikes home — but once again, not at the policy level, as
stated above. Secondly, there is the issue of consent and its validity. The
consent requirement is premised on the fact that the parents are the ones who
have the best interests of the child (here the fetus) at heart. But does such
a premise obtain when an abortion (presumably immoral) is being planned? Does
a mother planning an abortion in the circumstances described have the best
interests of the fetus at heart? I think not. Thirdly, there is the possible
change of mind of the mother. Allowing experimentation prior to abortion — that
is, experimentation that is potentially risky or harmful to the fetus — prejudices
the freedom of the woman to change her mind about the abortion, and thus con-
stitutes an infringement on fetal rights for this reason alone, if for no other.
To those who do not share my evaluation of fetal life, these considerations will,
of course, seem marginally relevant at best.
(b) During Abortion. Once again, a distinction: If the abortion is
morally legitimate, then granted appropriate proxy consent, experimentation could
be legitimate if it left the fetus in no worse position during its dying than it
is in as a result of the abortion. If, however, the experimentation leaves the
fetus in a worse position (e.g., pain), then it is equivalent to illegitimate
experimentation on the dying. If the abortion is not morally legitimate, then
experimentation on the fetus raises two of the points mentioned in the above
paragraph, namely, cooperation and invalidity of consent. The question of "dis-
cernible risk" seems meaningless morally, since it seems meaningless to speak of
exposing to risk one who has already been inserted into a lethal situation.
(c) After Abortion. The fetus may be either living or dead. If
the fetus is still living and the abortion was morally legitimate, then experi-
mentation seems morally legitimate if it induces no pain or discomfort. For if
the fetus may be constructed to consent to experiments where no discernible harm
is involved, and if he is in a situation (lethal) where the difference between
discernible harm or risk is meaningless, then he may be legitimately constructed
to consent — given appropriate proxy consent. If the fetus is still living and
the abortion was morally illegitimate, then the above issues (cooperation, con-
sent) could intrude to prevent any morally legitimate proxy consent.
B. The Fetus Extra Uterum
(1) Spontaneous Abortion. The fetus may be either living or dead. If
it is dead, there should be no moral objection to experimentation. If the fetus
is living, the same conclusion obtains providing experimentation imposes no pain;
5-6
for the fetus may be legitimately constructed to consent to experiments involving
no discernible risk, and he is in a situation (lethal) where the distinction
between no discernible risks and discernible risk is meaningless.
(2) Induced Abortion. Here the same things are to be noted that were
stated above about a fetus in utero after abortion.
In summary, then, within the parameters of my evaluation of fetal life,
fetal experimentation would be clearly justified, with appropriate safeguards,
distinctions and consent, where the abortion is spontaneous or has been justi-
fiably (morally) induced. Where it has been induced without moral justification,
I believe there are moral objections of various sorts against experimentation.
However, since these objections are premised on the moral character of the
abortion, and since this is a difficult (at times) determination in itself, and
since the ultimate judgment will hardly be shared by a majority, these objections
will be extremely difficult, indeed impossible, to formulate in policy proposals
on fetal experiments. Moreover, one can question whether restrictions on fetal
experiments rooted in such considerations is the best way to highlight the moral
illegitimacy of the abortion. ...
Where experimentation is morally justified, it is so because of the
legitimacy and sharp limitations of proxy consent, extrapolated from the legiti-
macy of proxy consent where children are concerned. I wish to emphasize this
point here. If proxy consent (with the clear limitations on the validity of
this consent) is not the basis for the moral legitimacy of experimentation on
fetuses, then the integrity of the individual will be "protected" not by soundly
reasoned constructions of what the fetus — or any human being--would consent to
because he ought, but by a very unpredictable and highly utilitarian assessment
of his value and worth as over against great (alleged) scientific and medical
benefits for others. Such an assessment does not provide but erodes — in a highly
technological, pragmatic society — individual protection. Thus the DHEW's origi-
nal but tentative version of "Protection of Human Subjects, Policies and Pro-
cedures"'^ stated: "The investigator must also stipulate either that the risk
to the subjects (children) will be insignificant, or that although some risk
exists, the potential benefit is significant and far outweighs that risk." In
such thought and language is the germ — and even more — of the subordination of
the individual to the collectivity. That germ is in the conclusion, to be sure;
but it is far more insidiously present and threatening in the very way of think-
ing, in the form of moral reasoning undergirding it. We call it utilitarianism.
And whatever the policy proposals this Commission recommends, it will have only
gotten mired in the cultural status quo if its conclusions root in a utilitarian
assessment of the value and integrity of man, fetal or otherwise.
Avoidance of this trap will not be easy. For if notable medical benefits
do not justify all experimentation, they are the only things that justify any
experimentation. And once that is said the tendency will be to give medical
benefits the preference. Furthermore, if fetal individuality and dignity do
not prohibit all experiments, they certainly prohibit some. It is the first
task of this Commission to discover the form and structure of moral reasoning
on which alone the proper protective balance can be based and spelled out in
policy proposals. That form and structure centers around proxy consent, its
legitimation and limitations.
5-7
4. ABORTION POLICY AND EXPERIMENTATION POLICY
I raise this issue prior to an explicit consideration of policy proposals
because I presume that legal or policy consistency is, at least to some extent,
a desideratum. From a moral point of view fetal experimentation and abortion
are in some respects separable issues. That is, even though a particular
abortion is judged to be morally justifiable, one could maintain that experimen-
tation on the living abortus is illegitimate experimentation on the dying. And
that is a different question from the morality of the abortion itself. There
are those who would convert such separability as follows: even though the
abortion was illegitimate, it does not follow that experimentation on the abor-
tus is also illegitimate. (I do not believe the matter is that simple, as noted
above . )
However, there is a point at which these issues converge, particularly in
the popular mind. This convergence is best seen at the policy level. Under
existing abortion law {Roe v. Wade, Doe v. Bolton) fetal life enjoys no protec-
tion during the first two trimesters of pregnancy, and even in the third the
compelling interest of the state is qualified by maternal health so broadly
defined that it would be difficult to convict anyone of an illegal interruption
of pregnancy anytime during pregnancy. The rationale for this policy is the
predominance of maternal interests, especially privacy, over "potential human
life." Now clearly, if fetal life is so totally unprotected with regard to its
very existence and survival, and on the grounds that it is only "potential human
life," then any policy restrictive of fetal experimentation must find other
grounds (other than present fetal humanity and rights) for its restrictiveness —
at least if legal consistency is to be preserved. For it is patently ridiculous
to stipulate that fetal life may be taken freely because it is only "potential
human life," and yet to prohibit experimentation on this same "potential human
life," especially when great medical benefits may be expected from such experi-
mentation. For such a prohibition would imply that the privacy or other interests
of one woman are of more value than the survival and health of perhaps thousands
of fetuses and infants.
I see no way out of this impasse where this Commission is concerned — except
to say that perhaps even legal inconsistency has its values. But the only value
perceptible to this commentator in such inconsistency is that it may be a first
step toward reassessment of the Court's "potential human life." That may be a
salutary step, but it reflects what appear to be the only two options open to
this Commission: to reaffirm, by implication, the Court's philosophy (as in the
dicta) in Roe v. Wade, or to establish proposals (restrictive in character) that
are at some point inconsistent with this philosophy. This latter alternative is,
in my judgment, the way to go.
5-8
5. POLICY ON FETAL EXPERIMENTATION . ■
In attempting to develop sound policies (what is feasible) on fetal experi-
mentation, I suggest that the Commission must keep two points in mind: moral
pluralism, and cultural pragmatism. A word about each:
A. Moral Pluralism .
Fetal life is variously evaluated, as the abortion decision shows. Even
though abortion and experimentation are separable, they are closely related as
I have pointed out. Therefore the Commission is in a very delicate position
and is faced potentially with another Roe v. Wade decision. In a sense the
Commission cannot win in its conclusions. If it allows fetal experimentation
without sufficient grounding and controls, it will alienate and galvanize those
identified with right-to-life positions. If it disallows fetal experiments
without sound and consistent reasoning, it will alienate and galvanize the
"liberal" and research communities. If it tries to walk a middle path with a
utilitarian sliding scale of costs and benefits, every decent ethician in the
country will be up in arms.
The only way out of this bind (and one which avoids utilitarian costs-
benefits theory) is tied to the notion of proxy consent. In other words, that
measure of proxy consent regarded as valid for children, should be the measure
of acceptable fetal experimentation. Where children are concerned, proxy con-
sent is legitimate where .the experimentation involves no discernible risks,
discomforts, or inconvenience — in human judgment. Beyond that the individual
must be free to consent for himself. Analogously, the same is true with the
fetus. If the experimentation involves no discernible risk, or, if the nonviable
fetus is dying and there is no pain, proxy consent may be regarded as legitimate.
(There is a moral problem, of course, with the legitimacy of proxy consent where
the fetus is about to be aborted or has been aborted. However, since the moral
legitimacy of the abortion itself is a highly disputed point in our society, the
legitimacy of proxy consent in these cases cannot be decisive at the level of
policy. Sc. , it is not feasible.)
This practical policy structure (centering on permissibility and controls
grounded in proxy consent) has the advantage of speaking to all segments of a
divided community. To those convinced of fetal humanity and protectability , it
says: nothing more or less is allowed on the fetus than on the child. To the
"liberal" and research community, it states the legitimacy and need of fetal
experimentation. To the ethical community it states that the legitimacy and
control of fetal experimentation is neither capricious nor utilitarian in
character, but soundly and rationally based in and controlled by an intelligible
principle.
B. Cultural Pragmatism
Our culture is one where technology, even medical, is highly esteemed;
moral judgments tend to collapse into pragmatic cost-benefit calculations; youth,
health, pleasure, and comfort are highly valued and tend to be sought and
5-9
preserved at disproportionate cost; maladaptations (senility, retardation, aging
process, defectives) are treated destructively rather than by adapting the envi-
ronment to their needs. These factors suggest that the general cultural men-
tality is one that identifies the quickest, most effective way as the good way.
Morality often translates into efficiency. This mentality constitutes the atmos-
phere in which the Commission's policies must be shaped. They are, I believe,
calculated to be threatening and inimical to a careful implementation of proxy
consent at the fetal-research level. Therefore, I believe that the Commission
will best serve the community if it bends toward more protection of individuals,
rather than more freedom for experimental research. The culture v/ill bend this
latter way, and the proposals ought to be conceived as a balancing influence,
not simply a reinforcing one.
If the above reflections are accurate, the task of the Commission (once
it has accepted the proxy-consent rationale for experimentation on fetuses) is
twofold: first, to spell out insofar as is possible what degree of risk may be
regarded, in broad human terms, as equivalent to "no discernible risk"; and
second, to detail the procedural demands that will best assure that this deter-
mination is realized in individual protocols.
The following points are suggested as an attempt to bring this tv.'ofold
task to the level of concrete proposals.
(1) The experiment must be necessary. Use of animals and dead fetal
tissue is not sufficient; the experiment is not repetitive (of work being done
elsewhere); proportionate benefits are reasonably anticipated.
(2) The onus of showing necessity is on the experimental researcher.
(3) There must De no discernible risk for the fetus or mother, or, if
the fetus is dying, there is no added pain or discomfort. (This excludes all
experiments that are aimed at determining what harm might come to the fetus,
and all experiments that prolong the dying process of the fetus) .
(4) The onus of showing no discernible risk is on the experimental
researcher .
(5) The above demands must be secured by prior approval and adequate
review of all fetal experiments. The reviewing group ought to include at least
some members outside of the research community. (There is a tendency, as the
literature shows, for researchers to minimize risk not only in terms of pros-
pective benefits, but also in terms of tne ability to "handle complications"
that may arise . )
If these policies appear to some to be too restrictive, it must be recalled
that we shall only know whether they are unduly restrictive if they are tried.
It is always possible to liberalize; it is much more difficult to retrench — and
retrenchment occurs only after rights have been exposed or violated. Where the
rights of others are even and only possibly at stake, the part of wisdom and
humanity is to try the less obvious, perhaps the more arduous but more conser-
vative (of rights) way.
REFERENCES
1. Micallef, Paul J., "Abortion and the Principles of Legislation," Laval
Theologique et Philosophigue 28:294, 1972.
2. Shinn, Roger L., "Personal Decisions and Social Policies in a Pluralist
Society," Perkins Journal 27:58-63.
3. Cf. especially Ramsey, Paul, The Ethics of Fetal Research, New Haven: Yale
University Press, 1975; Walters, LeRoy, "Ethical Issues in Experimentation
on the Human Fetus," Journal of Religious Ethics 2:33-75, 1974.
4. Ramsey, Paul, The Patient as Person, New Haven: Yale University Press,
1970, pp. 27-40.
5. May, William E., "Experimentation on Human Subjects," Linacres Quarterly
41:238-252, 1974.
6. Curran, Charles E., "Human Life," Chicago Studies 13:293, 1974.
7. O'Donnell, T. J. , Journal of the American Medical Association 227:73, 1974.
8. McCormick, Richard A., "Proxy Consent in the Experimentation Situation,"
Perspectives in Biology and Medicine 18:2-20, 1974.
9. Cf., O'Donnell, op. cit.
10. Cf . , Curran, op. cit.
11. Cf . , McCormick, op. cit.
12. Beecher, H.K., Research and the Individual, Boston: Little, Brown, 1970.
Cf. also Curran and Beecher, Journal of the American Medical Association
210:77, 1969.
13. Ingelfinger, F.J., New England Journal of Medicine 288:791, 1973.
14. Cf . , Beecher, op. cit.
15. Archives of Disease in Childhood 48:751, 1973.
16. Cf., Ramsey, Walters, op. cit.
17. Federal Register 38:31738, 1973.
MORAL ISSUES
IN FETAL RESEARCH
Paul Ramsey, Ph.D.
PAUL RAMSEY, Ph.D.
Dr. Ramsey is presently Harrington Speare Paine
Professor of Religion at Princeton University.
PD 304210-5
Moral Issues
in Fetal Research
We are asked to give some attention to the concept of fetal death. I take
the Commission to mean that until we define what we mean by a fetal human subject
that is "living" yet "previable" we cannot even begin to discuss whether or in
what manner such a being ought to be used in human experimentation. Here there
seems to be an unfinished task of first importance: a conceptual task, the task
of defining the fetal human subject.
The parameters needed to locate this new potential subject (whether of
ethical or unethical human experimentation) must consist of a baseline and an
outer limit. The subject must be circumscribed before and after. On one side,
physicians need to tell the difference between a dead fetus and a live one. On
the other side, they need to tell the difference between a previable fetus/
abortus and a possibly viable infant. We need agreement in general about those
indices or signs of life which physicians should use in rightly stating that a
fetus/abortus has died (a declaration of death) no less than physicians need to
know how best to tell the onset of viability, and where the latter line should
be drawn for research purposes. In responding to the question of fetal death,
I shall address myself to both sides of the descriptive definitional problem.
These are practical questions — about vital signs and viability signs.
One line only — the viability line — does not define a class. (Neither does the
life line.) One cannot make salvageability do work for both sides of the param-
eters needed. To declare that a fetus or abortus is not viable is never the
same thing as to declare that a living previable fetus/abortus has died.
This the Commission has recognized in asking for comment on the concept
of "fetal death." In context, I take that not to be a query about the "meaning"
or definition of life and death in any ultimate sense. Rather the question is
a practical one, namely, how to tell the difference between a dead fetus/abortus
and a live one when we are thinking about bringing the latter under procedures
that entail classifying it as a human research subject.
The answer seems clear enough: the difference between the life and death
of a human fetus/abortus should be determined substantially in the same way
physicians use in making other pronouncements of death. To adopt in this
instance other criteria, or to ignore the vital signs (if present in the fetus)
ordinarily consulted in other such declarations, would open the medical research
profession to charges of ad hoc-ery, special pleading, and bad faith for research
purposes.
6-1
Dr. Bernard N. Nathanson gave the only intellectually coherent reply that
can be given to the Commission's question to us. He wrote (on another but
related issue) :
"The Harvard Criteria for the pronouncement of death assert that if
the subject is unresponsive to external stimuli (e.g., pain), if the
deep reflexes are absent, if there are no spontaneous movements or
respiratory efforts, if the electroencephalogram reveals no activity
of the brain, one may conclude that the patient is dead. If any or
all of these criteria are absent — and the fetus does respond to pain,
makes respiratory efforts, moves spontaneously and has electroenceph-
alographic activity — life must be present."^
Nathanson was not arguing that these criteria would put the living fetus into
the class of infants. He was rather citing the indications for believing that
the fetus/abortus before viability is reached was already "human life of a
special order" readily distinguishable from an entity that has lost those signs
(fetal death), or never had them.
True, the 1973 NIH proposed guidelines^ studiously refuses to speak of
the previable fetus as "living" or having "life." But one cannot contrast our
siibject with a dead fetus without presuming to know signs of life and to rec-
ognize their absence before viability. Moreover, this document's twin prohibi-
tion of experimental procedures which artificially maintain or which of them-
selves terminate heartbeat or respiration in a fetus judged to be previable,
reaches back to prevent intervention upon one of those vital signs that must
surely be used to distinguish fetal life from fetal death, namely heartbeat.
I shall not comment here on the inclusion of respiration except to say that I
thought capacity to expand the lungs was a chief indication of possible via-
bility. By studiously refusing to speak of a previable fetus/abortus who may
still be medically "alive" and by leaving the determination of viability entirely
to the discretion of physician researchers (not even excluding abortuses with
respiration from being deemed previable and entered into experimentation) , the
American guidelines can be faulted for lack of definitional clarity. Indeed,
if and only if the previable fetus is human, unique for certain purposes, and
alive in significant medical respects — i.e., if it is not dead — could claims
be made that researchers need the knowledge uniquely to be gained by using the
fetus/abortus while it is still living, growing and reacting as a tiny, whole
fetal human being or entity. Finally, the 1974 DHEW-NIH revision^ of these
guidelines — for all its continuing austere definitional reluctance to say "life"
or "alive" — refers to "the whole fetus or abortus, functioning as an organism
with detectable vital signs." This is enough to show the way to a proper con-
cept of fetal death.
The guidelines developed in Great Britain and the United States have all —
in differing ways — recognized the need to define this novel human research sub-
ject by distinguishing it both from a dead fetus on the one side, from a viable
baby on the other. The "Peel Report"" in force in Great Britain distinguishes
a live fetus from a dead one by stating that before viability the former "shows
some but not all signs of life." The 1973 proposed NIH guidelines excluded the
following from the meaning of abortus research (to which question, regulations
were addressed for the protection of "human subjects"): "the placenta, fetal
material which is mascerated at the time of expulsion, a dead fetus [sic] , and
isolated fetal tissue and organs excised from a dead fetus." Impliedly, a
distinction can be made between a certainly previable abortus and a dead one.
It can be made in practice by reference to vital signs ordinarily used in
findings of death, with the addition of tests or findings that may be unique to
the practice of fetal medicine.
I assume then — with Nathanson — medicine's ability to determine fetal death
in ways that are not inconsistent with other findings of death. I want next to
remark upon the other side of the definitional task, the viability line to be
drawn in defining this new human research subject.
The "Peel Report" states that no fetus of more than 20 weeks gestational
age or more than 300 grams (3/4 lb.) in weight shall be eligible to be made a
research subject. That was a definition on the safe side of viability; a defi-
nition of viability for research purposes. During 1971-1973 (it was disclosed
in April 1973), NICHD's Human Embryology and Development Study Section had
under discussion a proposal that a fetus eligible for research "must meet at
least two out of three criteria: it must be no older than 20 weeks, no more
than 500 grams (1.1 lbs.) in weight; and no longer than 25 centimeters (9.8
inches) from crown to heel." * It is of first importance that we go back to the
beginning and reinstate one or another of these descriptions of our new research
subject on the safe side of viability. I suggest that the Commission's first
task is simply this definitional one of locating the subject of its delibera-
tions between fetal death, on the one hand, and on the other, viability defined
for research purposes on the safe side of the line or span of possible viability
that physicians use in decisions relevant to promoting the life of the fetus/
neonate.
In the August 1974 revision of the NIH guidelines. Secretary Weinberger
stated that "the Department does not believe that the use of weight, size,
gestational age and/or cortical activity is a valid substitute for the judgment
of a physician" in distinguishing between a viable and a nonviable fetus.
But the issue is not viability for general medical purposes; rather the
need is for a definition of viability for fetal or abortus research purposes.
Of course, the fetus is generally viable at all stages unless it is removed
from its natural environment. In face of that actual viability at all stages
of development, in abortion practice we define viability in another and an arti-
ficial way. In the matter of research practice we need another, more or less
artificial, definition of viability: eligibility and noneligibility for research
purposes defined at an upper limit safely short of the span of possible or actual
viability.
Researchers should be the first to insist that abortuses eligible to be
entered into medical experiments be defined on the safe side of possibly viable
birth weight, crown-rump length, or gestational age. They should want to be
seen always to do right by not even proposing research with fetuses except within
an outer limit on the safe side of viability (itself to be updated with future
progress in medical technology) .
6-3
Nor can it be good public policy or good intraprofessional medical policy
to leave standing any possibility that medical researchers could be (or could
seem to be) experimenting on possibly "viable" babies in the ordinary and per-
meable meaning of that expression. The point is not the meaning of viability
for the purpose of decisions promoting the saving of life or allowing to die
or undertaking investigations connected with diagnosis or treatment in the prac-
tice of fetal medicine or pediatrics. On those matters, doiibtless, as Secretary
Weinberger said, there is no "valid substitute for the judgment of a physician."
The point is rather drawing a line on viability/eligibility for research pur-
poses. The point is the completion of the definition of this new class of pro-
posed legitimate research subjects. There is nothing morally at stake in
building such a fence — except that it should prevent any researcher from doing
nonbenef icial experiments with a viable infant by mistake, and it would establish
in public and medical policy the assurance that this will never be done.
I do not say that, below stated weight, crown-rump length or gestational
age, abortus research is justified. I do suggest that we need measurable limits
beyond which it clearly is not. I have simply suggested the completion of the
definition of this new class of proposed human research subjects — on the side
next to infancy and some distance away from the line that can be drawn between
a living fetus/abortus and a dead one.
Such are the parameters properly circumscribing the living yet previable
fetus/abortus. To state these dimensions or sketch of the class of possible
human research subjects we are talking about is only the beginning — the precon-
ditions— of a proper analysis of ethical practice in fetal research. As that
analysis proceeds in the Commission's deliberations and in the public forum,
some sorts of experimentation ought surely to be excluded. Perhaps many research
designs may prove incompatible with protections due the fetus. Perhaps all
experimentation should be forbidden except for controlled observation or inter-
ventions foreseen to bear no risk of harm, etc. But none of these upshots from
serious ethical reflection and from careful drawing of lines between the morally
permissable and the morally impermissable are any excuse for not first defining
what we are talking about using in research.
In short, the parameters tell us nothing yet about the accompanying regu-
lations for the protection of this potential new class of human subjects. The
first parameter acknowledging the livingness of a previable fetus only keeps us
from confusing the issue before us with what should or should not be done with
a dead fetus or fetal organs and tissue (an entirely different question) . The
second parameter only keeps us from doing by mistake something we meant not to
be talking about, namely nonbenef icial experimentation on possibly viable neo-
nates. To define previability on the safe side for research purposes need not
mean that then all is permitted, or that anything is as yet permitted. We have
as yet said nothing about what should be done between the parameters, between
the dead/living fetus line and the previable/viable line. On the latter, I
simply urge that we need some numerical or measurable definition on the safe
side of viability even if then we go on to say that, to be ethical, research
ought never to prolong or directly terminate vital signs, or ought not to be
done to ascertain harm to the fetus, or ought not to be done if there is any
discernable risk — or if we go on to say that between the parameters there are
6-4
no limits to what may be done with the live previable human fetus/abortus except
those limits upon research procedures that stem from promising benefits to come.
The more I study the paragraph in which the 1974 DHEW-NIH revised policy
reaffirmed the original 197 3 view that "heartbeat and respiration are, jointly,
to be the indicators of viability," the more I am persuaded that the Department
and its respondents are making the same simple mistake. Both are trying to make
the viability line do the work also of the life/death line in determining the
parameters of this potential new class of human research subjects. Consider the
following summary:
"Some respondents suggested specific criteria such as birth weight,
crown-rump length, or gestational age, similar to those used in
Great Britain, such criteria to be reviewed and reissued periodi-
cally by the Department .... Some respondents urged that pres-
ence of fetal heart beat be definitive (whether or not there is
respiration) while others urged that identifiable cortical activity
be specified as an alternative sign of viability. Others objected
strenuously to any distinctions as to the nature of fetal life,
holding that the physician's obligation should be the same to any
fetus regardless of weight, size, or age of gestation."
Now, that passage strongly suggests that everyone has fallen prey to a play on
words. "Viability" in its current meaning is only one of the meanings given
in the Webster's New International Dictionary (Second Edition): the "quality
or state of being viable" (the latter word defined as born alive or capable of
being born alive). However, another meaning reads: "ability to live, grow and
develop; as the viability of certain grains under dry conditions." Evidently,
the first is the meaning of "viability" when the word is currently used as a
term of medical art. Evidently also the foregoing statements play on a con-
fusion of that with the second meaning.
By studiously refusing to speak of the previable fetus/abortus as "alive"
or having "life," the Department subtly insinuates that a viability line can
also do the work of a life/death line. Then, in order to oppose salvageability
looming here as the beginning of a physician's obligation to the fetus, some
respondents were led into a similar, if opposite (and also verbal) error. They
want to draw other lines on the beginning of life in the fetus (in the relevant
sense of the beginning of or a new stage in the physician's duty to protect the
fetus from harm) , and they are reported to have done this by suggesting alter-
native definitions of "viability." Some said fetal heartbeat should be defini-
tive— as an alternative sign of "viability." While certainly heartbeat alone
is no test of "viability" in its going meaning, that might reasonably be taken
to be among the determinants of fetal life or death. Some suggested cortical
activity. Again, if EEG shows not only brain activity but also the beginning
of cortical brain activity during fetal development, that was to locate another
determinant of fetal life or death. (If full development of the cortical regions
of the brain was meant, it was a determinant of infant life or death, and an
indicator of death not yet adopted in the case of other human beings.) Those
who strenuously objected to any measurable criteria for viability/eligibility
for research purposes were really saying that only the life/death line matters.
6-5
Where there is life, whatever its size or age, there is hope, and physicians
are unqualifiedly obliged to save, aid and protect that life from harm. Only
those who proposed to follow the British precedent may have had in mind the
need for both parameters in circumscribing and defining this potential class
of new human research subjects.
Citing Nathanson, I have urged that the criteria for fetal death cannot
be inconsistent with the indicators of death applicable to other forms of human
life. There may be additional tests, or variants of the common criteria, which
fetologists may propose. But in the present instance, "not inconsistent with"
other declarations of death is well-grounded in the fact that the fetus is more
like a human infant than it is like a human embryo, blastocyst or zygote. The
Commission is not called upon at this time to jump into the nettle of determining
embryonic life or death, or the death of blastocyst or zygote.
Moreover, those who argue that a physician's obligation is the same at all
stages of fetal life were not arguing that fetal death does not cause that obli-
gation to cease. In opposing the adoption of an outer parameter of viability
for research purposes, they were stating a view about the impermissability of
many or all forms of human research between those or other parameters. It is
true that they and they alone of all the respondents need only a life line; they
need no other parameter to state their views on fetal research. The rest, as
we have seen, fall into the error of using only a proposed viability line (blur-
ring the need for a different life line also) in order to open the door wide to
fetal research before viability without having to do some difficult thinking
about medicine's duty when considering this form of human life as a potential
experimental subject.
I urge, however, that a clear and safe outer boundary serves only a prac-
tical function, to be sure a very important one. It need not be question-begging
or value-laden for what may subsequently be deemed morally permissable research
using human fetuses that while not yet dead fall within that outer boundary.
My proposals to the Commission draw upon our extant medical ethics,
including the British "Peel Report" and the paragraphs on fetal research in the
1973 and 1974 versions of "The Protection of Human Subjects" generated by DHEW-
NIH.
1. U.S. medical research policy should contain a provision that "no pro-
cedures be carried out during pregnancy with the deliberate intent of ascer-
taining the harm that they might do to the fetus" (Peel) . Ethically, that seems
to me clearly a different research intention and action than "a medical prac-
titioner may carry out procedures on the mother with the deliberate intent of
ascertaining the benefit these might do to the fetus, even though the fetal
research subject is not likely to benefit because its abortion is in prospect."
For one thing, since both interventions — the beneficent one as well as the
harm-ascertaining one — are bound to carry some additional risks, the total harm-
fulness may reasonably be expected to be greater from the latter than from the
former procedure. That is an objective morally relevant consideration.
Still the choice between these alternative provisions rests mainly on a
subjective morally relevant consideration, namely, the intention (and not alone
the action) of the researcher. The "virtues of the moral agent" is an important
part of general ethics, and not "action guides" alone. Likewise, the "ethical
physician" is an important consideration for medical ethics, and not "codes of
conduct" alone. "Do not harm" encompasses also "intend to do no harm." How
can harm to the fetus be ascertained without a deliberate intention to do harm
to ascertain it?
2. The foregoing regulation in force in Great Britain is paralleled in
the apparently categorical prohibition of fetal research in utero in anticipation
of abortion in the first (1973) version of "Protection of Human Subjects" — which
however, opens up the question to which I believe the Commission must address
itself, namely the determination of a permissible degree of risks of harm even
from procedures a beneficent researcher may undertake for beneficent goals.
The 1973 NIH guideline states that "no experimental procedures entailing
risk to the fetus be undertaken in anticipation of abortion."
I have elsewhere argued that the experiments at Boston City Hospital
testing which of two antibiotics would be the more effective in protecting from
syphilis the fetuses of future mothers with penicillin allergies was ethical
research under either the "Peel" rule or the proposed American regulation of
fetal research in utero. ^ Still the subjective British rule needs to be supple-
mented by the objective weighing and limitation of risks suggested by the Ameri-
can guideline. Both should be included in U.S. public medical policy.
Here lies a creative frontier for the Commission's leadership — in spelling
out the meaning of this second provision so far as it is possible to do so — if
fetal research policy is to be based on sound moral grounds, and is to maintain
contact with our tradition of medical ethics. After all there is a difference
between experimental procedures having "no discernible risk," those having "no
discerned risk," those having "discernibly no risk," and those having only
"negligible risk" or "no conceivable risk." And how statistically negligible
must a "negligible risk" be to be morally negligible?' Even the Commission's
choice of language (if no one can go further) will be exceedingly important in
bracing the ethical researcher to the standard he should hold himself to in
conscience, not to speak of Ethical Review Boards. Carefully drawn, protective
language is needed — if for no other reason than to provide a benchmark against
which to "measure" the justifying reasons found (such often is the claim) in
exceedingly great benefits expected to come. Otherwise the human fetus will
become the most unprotected "primate" in medical research. (I refer to the
perturbation aroused among the generally nonantivivisectionist part of our popu-
lation from viewing primate experiments on piiblic television; the troubling
question awakened was: Has anyone even asked the question how important must
the benefits be to warrant doing such things to another living being close to
us in nature and resemblance?)
6-7
3. It is in order for me to insert here a parenthetical paragraph indi-
cating the appeals and warrants cited by the British committee and by the drafters
of the 1973 U.S. guidelines in support of proposals (1) and (2) above.
The "Peel Report" appealed at once to the criminal law to support its view
that "the protection afforded to the fetus is continuous and is not abrogated by
the fact that it may be the intention at the time of the affliction of the injury
that the fetus should be prevented by a subsequent abortion from attaining life."
Therefore, "even if the mother is willing to consent to such an experiment," that
too would not abrogate the protections afforded the fetus.®
The 1973 U.S. guidelines appealed directly to our tradition of medical
ethics to obtain the same foundation for its rule. "The recent decision of the
Supreme Court on abortion does not nullify, so far as medicine is concerned, the
ethical obligation to protect the developing fetus from avoidable harm," even if
that harm is lesser than the planned abortion. Why not? Answer: "Respect for
the dignity of human life must not be compromised whatever the age, circumstances,
or expectation of life of the individual. Therefore, all appropriate procedures
providing protection for children as subjects in biomedical research must be
applied with equal rigor and with additional safeguards to the fetus" (emphasis
added) .
In my opinion the philosophy of ethics and the medical ethics undergirding
the Commission's recommendations should be consonant with the foregoing. Some
indirect consequences of adopting these or similar fundamental principles are
pointed out in the footnote. ^
4. Live Abortus Research. The 1973 NIH proposed policy states two paral-
lel prohibitions: "If the [attending] physician determines that the fetus is not
viable, it is not acceptable [for the researcher] [1] to maintain heart beat or
respiration artificially in the abortus for the purpose of research. [2] Experi-
mental procedures which of themselves will terminate respiration and heart beat
may not be undertaken."
In the 1974 revision only the second of these provisions remains: "Experi-
mental procedures which would terminate the heart beat or respiration of the
abortus will not be employed." The first provision is reversed to read: "Vital
functions of an abortus will not be artificially maintained except where the
purpose of the activity is to develop new methods for enabling the abortus to
survive to the point of viability."
Everything depends on the meaning of "the abortus" in the last statement.
Does "the abortus" mean that particular abortus, the subject of that research
effort further to develop lifesaving techniques? If so, the provision allows
the artificial maintainance of the life of an abortus only in the case of inves-
tigational therapy, i.e. , experimentation related to efforts to promote the life
of particular abortuses with whom this may be learned. There is no ethical
objection to be lodged against such experimental treatments, except to say that
physicians ought not to take extraordinary affirmative action to save prematures
at cost of their grave injury from the procedure (and here there truly is no
substitute for the discretion of the physician) .
6-8
But "the abortus" in the statement above could mean abortuses as a class.
In that case the new methods of saving prematures to the point of viability
(otherwise expressed: new methods of pushing back the viability line still
further) would be sought solely for the sake of abortuses other than the human
research subject. There would be grave moral objections to be lodged against
that. I will mention only one. Such nonbenef icial research extending an abortus'
life is bound to do it damage. The protocols would have to stipulate that once
the procedure is perfected to the point of prolonging the life of the subjects
for, say, a week or two the experiment should be stopped, and the technique there-
after should be used only in trial therapeutic efforts to save abortus subjects
that already are close to viability. ^
In short, stopping the procedure would have to be a part of the experimental
procedure, if benefit to abortuses or prematures as a class is the main objective.
But then the revised guidelines prohibit that: "experimental procedures which
would terminate the heartbeat or respiration of the abortus will not be employed."
The planned termination of an experimental procedure — to avoid bringing a proce-
durally damaged abortus to the point of viability--cannot be excluded from the
meaning of that statement. If the 1974 revised guidelines were adopted, we can
anticipate a number of salvage experiments in which cannulas "inadvertantly" slip
and the subject dies.
If benefit to prematures as a class was meant, I rather think it would be
better, candidly, also to allow experimental procedures that terminate vital signs
in the human abortus subject. Was that prohibition retained only because the
public would not "understand" or accept the direct killing of still-living abort-
uses for research purposes? It also seems likely that on the other reading — "the
fetus" meaning a particular fetus submitted to therapeutic investigational efforts
to save it — a number of experiments will also "inadvertantly" come to an end, if
the lure of research benefits to other prematures comes to outweigh caution about
serious damage to the particular abortus under a physician researcher's care.
I would urge that the two parallel prohibitions in the 1973 NIH guidelines
be adopted, or else that the ambiguities and dilemmas introduced by the 1974
revision should be removed by a clear statement that the development of salvage
procedures, which maintain vital signs that otherwise would cease, can be
researched only with a physician's patients as aborted or premature experimental
subjects in connection with efforts consistent with the promotion of their lives.
5. It was certainly a symbolic flaw, and a flaw of some practical conse-
quences, that the Senate bill's reference to fetal research "whether before or
after induced abortion" was retained in the final language of the National
Research Act which established the Commission. For it is only in the quantity
of experimental subjects made available, and here rather than abroad, that there
is significant linkage between current abortion practice and the moral issues
involved in using living human fetal subjects in medical experimentation. The
products of spontaneous miscarriages, if previable and not yet dead, place the
same (or no) moral claims upon medical practice and upon the human community
generally.
6-9
Even fetal research in utero can be done and apparently has been done in
cases where the women were not planning abortions. The early pages of
Dr. M.H. Pappworth's Human Guinea Pigs ^° describe some rather astonishing impo-
sition of risks upon the fetus in situ and upon pregnant women that was not done
in anticipation of abortion. Undoubtedly, however, the wide practice of abortion
has freed up experimental designs especially in the case of fetal research in
utero with abortion in prospect.
In cases of live abortus research ex utero, however, a simple "thought
experiment" may help to separate the question of the morality of such research
from the question of the morality of abortion. One can imagine that abortus
research ex utero is proposed to be done only on products of spontaneous abor-
tions and on living abortuses that result from entirely justifiable abortions.
Let the abortion be just and necessary, however tragically necessary, e.g., to
save the mother's life, or whatever any member of the Commission happens to
believe is the sort of, or occasion for, abortion he or she would entirely back
doing morally. This is one way to keep these issues separate, as they should
be. For the question of the morality of fetal research is what, if any, moral
claims should rightfully be made in behalf of the fetus, even — perhaps espe-
cially— while it is dying from spontaneous abortion, and even — perhaps espe-
cially— when it is already condemned by an abortion decision or is dying from
that decision already set in course.
For these reasons, my own view is that the ethical standards applicable
to fetal research are the same as we would subscribe to in the case of proposed
research on the unconscious, on the dying (in cases of spontaneous abortion) or
on the (perhaps justly) condemned (in cases of abortion) or in experimentation
with children. (The latter was in fact the position taken by the original or
1973 NIH policy.) My argument that these are the applicable standards is in the
public forum and available to the Commission.
Let me, instead, cite in conclusion the best recent article by an ethicist
who favors, more than I do, placing uncomprehending subjects at some degree of
risk, namely, Richard J. McCormick, S.J., "Proxy Consent in the Experimentation
Situation. " ^^ Father McCormick uses the expression "vicarious" consent for
situations in which parents or another proxy authorize operations or investi-
gations connected with treatment. That is not at issue in fetal research; at
least in my view no objection can be lodged against fetal research related to
promoting the life of the fetus. I mention it only to point out that, as an
ethician. Father McCormick wishes to say that "vicarious" consent is valid not
because the child would want investigational therapy, but because he should do
so. Likewise, in the case of "presumed" consent to nonbenef icial experimentation,
he believes that is valid if proxies correctly construe not what the uncompre-
hending human research subject would want or does desire, but rather is some-
thing he should will to do.
The question, then, in regard to research with children and with the fetal
human subject (if "all appropriate procedures providing protection for children
as subjects in biomedical research must be applied with equal rigor and with
additional safeguards to the fetus" and if we ought not to regard respect for
human life as a variable functioning with "expectation of life" — 1973 NIH policy)
6-10
translates into the question: What ought those subjects to want, as social
beings for the long or brief time they have in the human community?
I draw the Commission's attention to this important article because any
theoretical differences between Father McCormick and myself (important as we
theoreticians fondly believe they are) has only quite narrow consequence in
indicating the range of practical action guides the Commission is charged to
formulate. The consent Father McCormick would "presume" or "construe" (based
on what the--in some sense — living human subject ought to want) is simply
experimentation beneficial to others that involves "no discernible risks, no
notable pain, no notable inconvenience, and yet holds promise of considerable
benefit" for other humankind. He quotes — in Latin, no less — parum pro nihilo
reputatur ("very little counts for nothing"). While I myself tend to believe
that any use of the fetal subject, children, the unconscious, the dying or the
condemned would be an abuse, I grant that there may be degrees of "no discern-
ible risk" that closely approximate my position. Apart from that refinement,
the signal thing to note is that Father McCormick and I agree that "one stops
and should stop precisely at the point where 'construed' consent does indeed
involve self-sacrifice or works of mercy .... The dividing line is reached
when experiments involve discernible risk, undue discomfort, or inconvenience."
Concerning a child — and I add, the fetal human research subject — McCormick says
that "he need not ought to want" real dangers; that awaits charitable self-
sacrifice which no one should presume to exact of another.
The moral basis legitimating "presumed" consent which McCormick endorses
leads precisely to my oyn location of the chief task of the Commission in for-
mulating fetal research policy (paragraph two above) . I respectfully suggest
that if the Commission follows the 1974 DHEW-NIH revision in making the facticity
of abortion crucial in its deliberations, that can only amount to seizing the
"golden opportunity" afforded by abortion to exact — and falsely to "presume" —
acts of charity from the fetus as a human research subject. That can only mean
a terrible distortion of medical ethics to date, and of the Jewish-Christian
tradition which was the foundation of its regard for the sanctity of human life
regardless of its age, condition or "expectation of life."
REFERENCES
"Deeper Into Abortion," tiew England Journal of Medicine 291 (No. 22): 1189-
1190, November 28, 1974.
By this and similar expressions I refer to the first published version of
"Protection of Human Subjects," Federal Register 38 (No. 221) : 31738-48,
November 16, 1973.
By this and similar expressions I refer to "Protection of Human Subjects,"
Federal Register 39 (No. 165) : 30648-57, August 23, 1974.
"The Use of Fetuses and Fetal Material for Research," Department of Health
and Social Security, Scottish Home and Health Department, Welsh Office,
London: Her Majesty's Stationery Office, 1972.
"Proposed Grant Code for Experiments on 'Viable Human Fetuses,'" Ob-Gyn News,
April 15, 1973.
Ramsey, Paul, The Ethics of Fetal Research, New Haven and London: Yale
University Press, 1975, p. 68. , , , ,,
A routine answer to this question will no longer suffice. In Helling v.
Carey, 519 P. 2nd 981 (Wash. 1974) , the Supreme Court of Washington held
physicians responsible for negligence despite uncontradicted expert
testimony that it was the universal practice of ophthalmologists not to
administer glaucoma tests to patients under age of 40 because the inci-
dence of glaucoma below that age is in the neighborhood of 1 in 25,000.
While "standard medical practice" holds that degree of risk to be negli-
gible, the court ruled to the contrary: "that one person, the plaintiff
in this instance, is entitled to the same protection, as afforded persons
over 40, essential for timely detection of the evidence of glaucoma
where it can be arrested to avoid the grave and devastating results of
this disease." The court held physicians accountable to "a standard of
reasonable prudence, whether it is usually complied with or not."
"Reasonable prudence" may not be the same as "common prudence," since
"a whole calling may have unduly lagged ..." Thus the court reached
out to protect patients under 40 for whom risk of 1 in 25,000 was for-
merly deemed "negligible."
First, the Commission thereby would avoid lending support to astonishingly
inept extrapolations from the Supreme Court's abortion decision that are
widely believed. It is often said that by that decision the Court opened
the door to any and all experimentation on the fetus or abortus in the
6-12
REFERENCES (Continued)
first and second trimester. In that decision, however, a woman's consti-
tutional right of privacy was brought against restrictive State legisla-
tion. It is very poor legal reasoning to say that a woman now has a
quasi-constitutional right to deliver an abortus into the hands of a
researcher or to cause potentially harmful experiments to be done on her
fetus in utero in anticipation of abortion or on her abortus if delivered
alive. Nor is there a constitutional right to the benefits of medical
progress; nor is a class action in behalf of anonymous future benefitees
apt to be brought, or succeed. The Commission is free to affirm the fore-
going principles of medical ethics. Indeed, an invitation to the Com-
mission to do so can be found in the fact the law is quite capable of
deciding one thing for one purpose, another in another connection. What
the law is when it is a matter of the fetus versus a woman's constitutional
rights is one question. What the law might say or ethics should say in
the matter of the fetus or abortus versus research is a quite separate
question.
Second, by reaffirming our tradition of medical ethics and basing its
recommendations on this (as did the 1973 NIH proposed policy) , the Com-
mission would incidentally give needed leadership to the medical profession
in closing a gap that has been left wide open in recent years. I have in
mind the ambiguity and uncertainty about the responsibility of physicians
toward potentially viable human life. In this uncertainty a number of
sticky legal cases have arisen, as is well known, and widespread doubt in
the public mind concerning what physicians deem their responsibility to
be toward viable lives that may fall under their care as a result of
abortion procedures.
The Commission's lead in reaffirming medicine's obligation to life
regardless of expectation of its longevity (plus a definition of viability
on the safe side) , would have important influence on the grey area into
which the near-viability fetus has fallen in the practice of medicine
generally.
I quote from an important legal analysis of one of the Boston cases:
"The Edelin prosecution may be explained as the result of a per-
ceived breakdown in professional self-regulation in late-term
abortions .... Thus Dr. Edelin can hardly argue in defense
that his effort to shut off the fetus' blood supply before removal
was justified as standard medical practice, for it is the ethics
of such practice which is being challenged. Resort to the legal
system occurred because of the unwillingness or inability of the
medical profession to engender sufficient consideration of fetal
interests in late-term abortions .... If [Dr. Edelin] dis-
regarded the interests of the fetus altogether, or made a judgment
that even if viable, its future was poor, then we may question his
6-13
REFERENCES (Continued)
ethics, the profession's inability to resolve such questions,
and find law an appropriate instrument to protect such interests."
— John A. Robertson, "Medical Ethics in the Courtroom," Hastings
Center Report 4 (No. 4) : 1-3, September, 1974.
Third and finally, it seems clear to me that only by affirming para-
graphs one and two above, along with the philosophy of ethics cited in my
paragraph three, can the Commission avoid the utter disarray and incoher-
ence in ethical and public policy reasoning that characterizes the 1974
revision of "Protection of Human Subjects." Perhaps I may cite chapter 9
of my The Ethics of Fetal Research (New Haven and London: Yale University
Press, 1975, pp. 75-87), for a full documentation of the disguised con-
fusion in saying that experimentation that will harm may be done if "part"
of an abortion procedure, in claiming still not to allow fetuses for whom
abortion is contemplated to be placed by research at greater risks than
fetuses in general while writing that into the Secretary's "exception"-
making power, and in published "corrections" that manage to say the same
thing. It does seem to me the Commission should show more perserverance
in rational analysis and greater rule-making prowess.
9. "The Human Fetus as Useful Research Material," Case Studies in Bioethics,
Hastings Center Report 3: 8-10, April 1973; Ramsey, Paul, The Ethics of
Fetal Research, New Haven and London: Yale University Press, 1975,
pp. 37-40.
10. Boston: Beacon Press, 1968.
11. Perspectives in Biology and Medicine 18 (No. 1): 2-20, Autumn, 1974.
EXPERIMENTATION ON FETUSES
WHICH ARE JUDGED TO BE NONVIABLE
Seymour Siegel, D.H.L.
SEYMOUR SIEGEL, D.H.L.
Dr. Siegel is presently Professor of Theology and
Professor of Ethics and Rabbinic Thought at the
Jewish Theological Seminary.
PD 304209-5
Experimentation on Fetuses
Which Are Judged to be Nonviable
In analyzing the ethical dimensions of the problem before this Commission
it is necessary to affirm certain basic principles:
1. A BIAS FOR LIFE
The most general principle which should inform our decisions in these cru-
cial matters is a "bias for life." This "bias" is the foundation of the Judeo-
Christian world view as well as the motivating force which undergirds medical
research and practice. It flows, for most people, from a theistic belief. How-
ever, it has been and can be affirmed by those whose views of reality do not
include the existence of God.-' The "bias for life" requires that all individ-
uals— most especially those involved in the healing arts — should direct their
efforts toward the sustaining of life where it exists; that means and procedures
which tend to terminate life or to harm it are unethical; and that where there
is a doubt, the benefit of that doubt should always be on the side of life.
Another implication of this "bias" is that any individual life which claims our
efforts and attention, and which is before us at this moment, has precedence
over life that might come afterwards. In certain situations, individuals are
called upon to sacrifice their lives or their comfort for future generations.
This is part of our character as members of the human race tied to those who
came before us and to those who will come after us. However, the burden of
proof is always upon those who wish to subordinate the interests of the individ-
ual presently before us for the sake of those who will come later. Experiments
for the "good of medicine" or for the sake of the "progress of knowledge" are
not automatically legitimated, if they cause harm to people now, because someone
in the future might benefit. What comes in the future is what the Talmudic lit-
erature calls "the secrets of the Almighty." This does not mean that we have no
responsibility toward the future. However, we have a greater responsibility to
those who are now in our care. These reflections do not, of course, preclude
the scientist's search. These are intended to make him more cautious in his
search.
This "bias for life" is exercised whatever the status of the life before
us is. The fact that the life is certainly to be terminated, that it is flawed,
or doomed does not preclude the activation of the "bias." This idea is expressed
in the 1973 U.S. Guidelines published by the Department of Health, Education and
Welfare: "Respect for the dignity of human life must not be compromised whatever
the age, circumstance, life expectation of the individual." [Emphasis mine.]
7-1
2. THE INDETERMINANCY OF THE FUTURE
Even the most expert scientific intelligence cannot predict the future
with certainty. This is especially true of medical science. Medical science
is replete with instances where certain experiments and treatments were adminis-
tered to human subjects with the expectation that these procedures would be
positive in their effect — only to turn out to be harmful. That means that when
a decision is made to permit experimentation on human subjects, there must be
present the utmost caution. Some of the experiments proposed would involve the
mother as well as the fetus. It is not impossible to predict that these very
procedures would have so changed the mother's organism as to preclude further
births or to have other untoward effects.
In speaking of the future effects of experimentation we should not over-
look the social consequences of policies in this area. Already the public is
beginning to believe that physicians are not merely the saviors of human life--
but also its destroyers. While this allegation is, of course, unfair, it is
still important to keep the social effects in mind when making policy in this
very sensitive field. This century has seen the consequences of the breach of
the notion of the sanctity of life. The Nazi horrors began with the legitima-
tion of the destruction of "useless" life and concluded with the most horrible
phenomenon of this or any other century. The ethicist, LeRoy Walters, has
stated: "An unexamined premise of both the British and the American policy
statements on fetal experimentation is that the consequences of such research
will be medical and that they will be good ... it is equally plausible to
argue that serious social consequences will follow such experimentation and
that these consequences will be mixed, at best."^
THE NUB OF THE PROBLEM: THE FETUS
In approaching our problem, the nub of the issue is the status of the fetus.
This problem can be approached medically, metaphysically and ethically.^ It would
seem that the two extreme positions which have been expressed in the literature
and public debate on this issue — though having much to commend them — do not seem
plausible.
The fetus does not seem to be identical with an infant. This is the view
of many religious and ethical traditions — including the rabbinic tradition. It
is supported also by common sense. The fetus has no independent life-system and
is literally tied to the mother. It has not developed the social and personal
qualities generally assumed to be part of being a full human being. This is not
a self-evident principle. B.A. Brody, in a recent article says: "the status of
the fetus and of whether destroying the fetus constitutes the taking of human
life . . . seems difficult, if not impossible to resolve upon rational grounds."*
Yet, it would seem that the weight of common sense is on the side of those who
wish to distinguish ontologically and ethically between a born infant and a fetus.
This means that feticide is not the same as homicide — that is, before viability.^
However, this does not mean that from an ethical standpoint there is no
difference between a fetus and a tooth or a fingernail of the mother — to be
disposed of as the mother wishes. It is indeed part of the mother's body — but
a unique part of the mother's body. It is only part of the mother's body which
is destined to leave the mother's body in order to take upon itself individual
and independent existence as a human being. This special status gives the fetus
certain rights that other organs of the mother do not possess. This is expressed
in the fact that Western religious thought has "ascribed a high value to prenatal
human life."^ Nor should we forget that even if we were to conceive of the fetus
as merely a limb of the mother, this does not imply that society has no responsi-
bility for what the mother does with her limbs. No civilized community would
allow individuals to capriciously cut off limbs from their own bodies — even if
they wished to do so. Of course, limbs can be amputated for the sake of the
whole individual. But this must be justified by the "interests" of the individ-
ual, and this "interest" must stand the test of common sense as well as medical
opinion.
What then is the status of the fetus, if it is not a whole individual or
mere tissue. The answer must be that the status of the foetus is that of "poten-
tial human life." Both Aristotle and Thomas Aquinas and many medieval thinkers
saw human life as a developing process from step to step. In the case of the
ancients it was from vegetative to animal to rational levels. However, it is
clear that successive stages of human ontogeny contain within themselves the
future stages.' That is to say, that all "higher" stages are present in potentia
in the "lower" stages.
The character of the fetus as "potentially human" raises it above the level
of "mere tissue." It therefore evokes within us a sense of responsibility for
its welfare as well as the welfare of the mother. Because it is not yet fully
human, the fetus has less rights than it would have if it were fully born. When
the fetus presents a threat to the mother's life or to the lives of its potential
siblings, then the mother has a right to protect herself against the fetus. That
is why most religious traditions permit abortion under some circumstances. When
one harms the fetus, however, "potential life is being thwarted."^
4. THE RIGHTS OF THE FETUS
The fetus, then, has potential human qualities and therefore ir has rights.
These rights are encapsulated in the demand it can make upon us to benefit from
our "bias toward life." This "bias," which makes us responsible to guard and pre-
serve life where it exists, this responsibility, to preserve the life of the
fetus, is not an absolute responsibility. In most civilized societies war is
legitimate even though it means the inevitable loss of life. But it is used to
serve a larger and more comprehensive aim of the society — its self-protection.
In the same way the fetus' right to our concern for its life is mitigated when
the fetus threatens someone elses life or health — his mother's or his prospec-
tive sibling's.* However, when there is no threat then the fetus' potential
humanity and his present life signs entitle him to benefit from the ethical
imperative to protect and revere life. This means that even before viability
7-3
and even when in utero the fetus has a right to expect those who interfere with
his own life-system to do so out of a consideration for the fetus' well-being
or the health of his mother. Those who do interfere with his life-system — phy-
sicians, experimenters, or others — are ethically permitted to do so only to help
the fetus sustain his life-system (unless, of course he is a threat to the mother
or his prospective family) . It must be stressed that this consideration involves
all fetuses — whether viable or not. To declare that a fetus or abortus is not
viable is never the same thing as to declare that a living previable fetus/abor-
tus has died.^
This does not mean that any kind of experimentation is prohibited. Experi-
ments, even when nontherapeutic, could be carried on which present no discernible
harm to either the mother or the fetus. Though the fetus can hardly give consent
to such experiments, those who are his guardians can give consent. Andre
Hellegers'° has described the many important experiments which could be carried
on within these guidelines especially those related to amniocentesis.
It would be most unfortunate if the respect for the life of the fetus were
related to the fact that he is soon to be aborted. Both the British and the
American guidelines''^ are insistent that a fetus in utero should not be the sub-
ject of procedures which can cause him harm even when he is destined to oblivion
through abortion. Paul Ramsey warns against skewing the medical ethical issue
involved here by the abortion issue .^^ It is possible to be against fetal
research in utero even when favoring abortion. The analogy has been drawn to a
condemned prisoner who is facing execution, or someone who is in extremis. Med-
ical ethical practice would condemn experiments on such individuals, even if they
were to redound to the benefit of scientific progress, unless such experiments or
procedures were designed to help the patient in some way. "Still I suggest that
someone who believes that it would be wrong to do nontherapeutic research on
children, on the unconscious or the dying patient, or on the condemned, may have
settled negatively the question of the morality of fetal research."'^
5. THE FETUS IN UTERO
Therefore the interventions that would be sanctioned when the fetus is in
utero would be those which (1) help the mother, (2) are harmless to the fetus,
or which (3) are designed to help the fetus in his own life-system. The latter
would be licit even if it resulted in negative outcomes — for it is ethical to
undergo procedures which have a good chance of success even when some risk is
involved.
The view expressed here reflects the prevailing opinion that "no procedures
be carried out during pregnancy with the deliberate intent of ascertaining the
harm they might do to the fetus." (Peel Commission).
Furthermore, it has been suggested that permission to initiate procedures
which will harm the fetus, even when there is an announced intention of abortion,
makes it impossible for the parent to change his or her mind about the fate of
the fetus. The possibility of reversal of decision about abortion should remain
to the last possible moment. This is a convincing argument to my mind.
7-4
The assertion that there might be a different ethical consideration in
reference to experiments carried out in the course of the abortion does not, in
my mind, merit approval. The circumstances of life do not mitigate the right to
benefit from our bias for life. To cite the analogy used above — even when the
rope is around the neck of the condemned prisoner he cannot be used for any pro-
cedure except that which is designed to bring him comfort or well-being.
6. THE FETUS EX UTERO
The living fetus ex utero , even when not viable, v/ould seem to have more
rights than the fetus in utero. When the fetus has been severed from his
mother's body, he can no longer pose a threat to her. There is no issue of the
woman doing with her body as she wishes, or the right of privacy, or the con-
sideration of the mother's health. It would seem, therefore, that the fetus'
right to enjoy our bias for life would be enhanced when he passes out of the
mother's uterus. Life is valuable wherever it exists. As such it evokes our
responsibility. The fact that the abortus is sure to die — it is, after all,
nonviable — does not mean that our concern for the life is diminished. Because
it will never be a real child, it is not, nevertheless, right to consider it
"nothing more than a piece of tissue."
We should understand "live" to include the presence of a heartbeat or any
other discernible sign of life. For example the Louisiana statute on the matter
reads: "A human being' is liveborn, or there is a livebirth, whenever there is
the complete expulsion or extraction from the mother of a human embryo or fetus,
irrespective of the duration of the pregnancy, which after such separation
breathes or shows any other evidence of life such as beating of the heart, pul-
sation of the umbilical cord or movement of voluntary muscles, whether or not the
umbilical cord has been cut or the placenta is attached."^*
The prohibition against experimental procedures on live abortuses should,
as the published guidelines suggest, concern both the artificial prolongation
of life systems such as heartbeats for the purpose of observation or the stop-
ping of any of the life signs. This does not mean that all experiments are
prohibited. Only those should be prohibited that do discernible harm to the
abortus. However, any procedure which breaches the dignity of the abortus such
as prolongation of life-systems or destruction of existing life-systems should
be prohibited. These considerations are in line with the guidelines suggested
by both the Peel Commission and the regulations proposed by the Department of
Health, Education and Welfare.
7. FETAL DEATH
The question of when can an abortus be presumed to be dead is a crucial
issue. There are those, who were cited above, who believe that in regard to
prehijmans, the only meaningful distinction is viability or nonviability . For
the reasons cited above, this approach is against the ethical canons of medi-
cine— which make no distinction of the prospects of the subject in regard to
7-5
his right to be treated with dignity and concern. While the dividing line
between viability and nonviability is crucial, the dividing line between death
and life is even more crucial. It is life — real and potential as well as being
part of the hitman species--that has an ethical claim upon us.
The best approach to this problem is that suggested by Professor Paul
Ramsey,-'^ "the difference between life and death of a human fetus/abortus should
be determined substantially in the same way physicians use in making other pro-
nouncements of death." He quotes Doctor Bernard Nathanson, who gave the only
intellectually coherent reply that can be given to the question put to us by the
Commission:
"The Harvard Criteria for the pronouncement of death assert that
if the subject is unresponsive to external stimuli (e.g., pain),
if the deep reflexes are absent, if there are no spontaneous move-
ments or respiratory efforts, if the electroencephalogram reveals
no activity of the brain, one may conclude that the patient is
dead. If any or all of these criteria are absent — and the fetus
does respond to pain, makes respiratory efforts, moves spontane-
ously and has electroencephalographic activity — life must be
present. "
These signs of life do not make the abortus into a viable infant. But they do
make it possible for the abortus to enjoy the fruits of our "bias for life."
It is interesting that the proposed DHEW guidelines do not present criteria
for fetal death. The Peel Commission defines death as "the state in which the
fetus shows none of the signs of life and is incapable of being made to func-
tion as a self-sustaining whole." These criteria have been criticized by
LeRoy Walters^® as being too vague. The last criterion, for example (being made
to function as a self-sustaining whole) might determine that infants are dead.
The idea of "signs of life," without designating what these "signs" are, also is
too vague. LeRoy Walters writes: "As a general formal requirement for defining
fetal death, I would suggest that any criteria developed for determining death
in human adults should be applied, insofar as it is technically feasible, to
the fetus. This requirement of simple biological consisteDcy would rule out in
advance the special pleading contained in hypothetical claims that the fetus is
dead because it is about to die or that the fetus was never really alive. "■'^
The concept of informed consent is essential in formulating guidelines
for experiments on human subjects. In the case of fetuses, this concept has
doubtful application. The fetus obviously cannot give consent. The consent
of the parents is made questionable by the fact that they have decided to ter-
minate their relationship to the fetus by consenting to an abortion. The con-
cept of consent is related to the concept of responsibility. Those who give
consent must in some way be ready to bear the consequences of their decision.
In the case of abortuses and fetuses this has doubtful applicability. There-
fore, it would seem that for the experiments that are legitimated, a special
board should give the requisite consent. This board would closely scrutinize
the proposed procedure and determine that there is no real risk in carrying it
out, that all precautions had been taken, and that there be strict separation
between the physician doing the abortion and the researcher.
PROPOSED GUIDELINES
In light of the above it is recommended that:
A. Research and experimentation on fetuses be limited to procedures
which will present no harm or which have as their aim the enhance-
ment of the life-systems of the subjects.
B. No procedures be permitted which are likely to harm the fetus,
even when the abortion decision has already been made, and even
where the abortion procedure has been initiated or is in progress.
C. When the fetus is ex utero and alive, no procedures should be
permitted which do not have as their primary aim the enhancement
of the life-systems of the fetus, unless such procedures present
no risk to the subject. This prohibition would also apply to the
artificial sustaining of life-systems for the sole reason of
experimentation .
D. Criteria for determining death in the fetus be the same as the
criteria applied to viable fetuses and other human individuals.
7-7
REFERENCES
1. The literature on this subject is enormous. For a summary of the views of
the Judaic tradition see Agus , Jacob B. , The Vision and the Way, an
Interpretation of Jewish Ethics, New York: Frederic Ungar Publishing
Co., 1966, and the bibliography cited there. It would, of course, be a
mistake to believe that this principle is so obvious as to be banal. We
have seen in our century whole societies based on opposite suppositions
such as to "kill is good."
2. Walters, LeRoy, "Ethical Issues In Experimentation on the Human Fetus,"
Journal of Religious Ethics 2 (No. 1) : 42, 1974.
3. For an interesting summary of the issues involved in the status of the fetus
see the work cited above by LeRoy Walters; Englehardt, H. Tristam, Jr.,
"The Ontology of Abortion," Ethics 84 (No. 3): 217ff, April 1974; Reback,
Gary L. , "Fetal Experimentation: Moral, Legal, and Medical Implications,"
Stanford Law Review, May 1974. For the Jewish views on the matter see
Feldman, David M. , Birth Control in Jewish Law, New York: New York
University Press, 1968; Jakobovitz , Immanuel, Jewish Medical Ethics,
New York: Bloch, 1959; and Aptowitzer, V., "Observations on the Criminal
Law of the Jews," Jewish Quarterly Review, Philadelphia, 1924, lllff.
4. Cited by Englehardt, op. cit.
5. See especially the book by Feldman, op. cit., and the discussion from a
philosophical point of view by Englehardt, op. cit.
6. Walters, op. cit., p. 48 and the literature cited there. Walters believes
that the religious opposition to abortion is based on theories of
ensoulment. Though this is certainly a factor, it would seem that the
intuitive feeling that we are dealing with a potential human being gave
birth to the religious attitude toward abortion.
7. Englehardt, op. cit., while citing and generally approving the Aristotelean
and Thomistic approach, however, draws the conclusion that it is not
ontologically correct to say that the future effect is present in the
present. He believes that each step is independent and ontologically
self-contained. Thus the fetus is really like a vegetable until it
develops the quality of movement. Then it is an animal until it shows
signs of rationality. This argument is not convincing to me. Poten-
tiality has an ontological status. That is: what I am to become is
present in what I am, for the simple reason, it seems to me, that I
cannot become what I will become unless I am what I am now. Therefore,
there is an organic relationship between what I am now and what I will
be later.
7-8
REFERENCES (Continued)
8. Feldman, op. cit . , 268ff.
9. See Ramsey, Paul, The Ethics of Fetal Research, New Haven and London: Yale
University Press, 1975. This new work will be a standard in the field
of fetal research.
10. Statement by Andre E. Hellegers, M.D., before Senate Health Subcommittee,
Senator Edward M. Kennedy, Chairman, July 19, 1974. Doctor Hellegers
is, of course, a distinguished physician as well as one who is concerned
with the ethical dimensions of the problems before this Commission.
11. These guidelines were formulated after the Supreme Court decision about
abortion.
12. Ramsey, op. cit.
13. Ramsey, op. cit., p. 30.
14. Cited in Reback , op. cit., p. 1199. . .
15. Ramsey, Paul, Statement submitted to National Commission for the Protection
of Human Subjects, 2ff.
16. Walters, op. cit.
17. Ibid.
7-9
8
ETHICAL AND PUBLIC POLICY ISSUES
IN FETAL RESEARCH
LeRoy Waiters, Ph.D.
LeROY WALTERS, Ph.D.
Dr. Walters is presently Director of the Center for
Bioethics, Kennedy Institute, Georgetown University.
PD 304106-5
Ethical and Public Policy Issues
in Fetal Research
"The Commission shall conduct an investigation and study of the
nature and extent of research involving living fetuses, the pur-
poses for which such research has been undertaken, and alternative
means for achieving such purposes. The Commission shall . . .
recommend to the Secretary policies defining the circumstances
(if any) under which such research may be conducted or supported."
"Until the Commission has made its recommendations to the
Secretary . . . the Secretary may not conduct or support research
in the United States or abroad on a living human fetus, before
or after the induced abortion of such fetus , unless such research
is done for the purpose of assuring the survival of such fetus . "
Public Law 93-348, sections 202b, 213
I shall begin by stating the conclusion of this paper, so that the upshot
of the following analysis is immediately apparent. A three-step argument forms
the core of the essay:
1. Nontherapeutic research on children should be permitted, if such
research involves no risk or only minimal risk to the subjects.
2. Nontherapeutic research on fetuses which will be carried to term
should be permitted, if such research involves no risk or only
minimal risk to the subjects.
3 . Nontherapeutic research procedures which are permitted in the
case of fetuses which will be carried to term should also be
permitted in the case of (a) live fetuses which will be aborted
and (b) live fetuses which have been aborted. . ,
I. SCOPE AND FOCUS
The legislation which created the Commission clearly focuses attention
upon "research involving living fetuses." Thus, this paper will not discuss
the problem of research involving the dead fetus, living tissues derived from
the dead fetus, or the placenta, fluids, and membranes. As noted below, the
term "fetus" will be used in a general rather than a technical sense to apply
to the living human conceptus (1) in utero from the time of implantation to
the time of delivery or abortion, and (2) outside the uterus from a point eight
days after fertilization to the point at which the organism is clearly viable.
8-1
II. DEFINITIONS
A. Fetus : the human conceptus in utero from the blastocyst stage to
delivery and outside the uterus from the blastocyst stage to the point at which
the organism is clearly viable. Beyond this latter point, an extrauterine organ-
ism would be designated an "immature infant" or a "premature infant."
B. Live or Living: possessing at least one of the standard signs of life,
namely, heartbeat, respiration, movement, or, in the case of the fetus, pulsation
of the umbilical cord.
C. Dead: the state in which the organism as a whole shows none of the
standard signs of life (in the absence of artificial life support systems) and
is not capable of being resuscitated. Individual tissues and cells may live on
after the organism as a whole is dead.
D. Viable : sufficiently mature to be able to continue to live apart from
direct connection with the mother, assuming standard neonatal care. I would rec-
ommend that for the sake of clarity this term be analyzed into three subcategories:
1. Clearly Viable: sufficiently mature to be able to survive in vir-
tually all cases, if no serious illness or malformation is present
(suggested estimate: birth weight of 2300 grams or more).^
2. Probably Viable: sufficiently mature to possess a 50 percent or
greater chance of survival, based on current national averages for
fetal survival (suggested estimate: birth weight of 1250 to 2299
grams) . ^
3. Possibly Viable: possessing a 49 percent or less chance of sur-
vival, based on current national averages for fetal survival. For
the purposes of this definition, the birth weight of a possibly
viable fetus must equal or exceed the birth weight of the smallest
fetus known to have survived through well documented medical records
(1975 estimate: birth weight of 500 to 1249 grams). ^
E. Previable or Nonviable : weighing less at birth than the smallest
recorded surviving fetus;'' clearly incapable of continuing to live apart from
direct connection with the mother, assuming standard neonatal care. A graphic
representation of the definitions proposed in D and E would appear as follows,
according to the suggested estimates:
previable
possibly viable
probably viable
clearly viable
500g 1250g 2300g
8-2
F. Therapy : the use of established and accepted methods of treatment to
meet the needs of a patient. ^
G. Therapeutic Research: the use of treatment methods which are not
established and accepted, with the primary intent of benefitting the patient
receiving the new treatment.* (Whether the new treatment in fact benefits the
patient is an important question but, according to the ethical codes which have
addressed the problem of clinical research, it is a secondary question.)
H. Nontherapeutic Research: the use of procedures which are not estab-
lished and accepted methods of treatment, with the primary intent of gaining
scientific knowledge or of benefitting persons other than the experimental
subject.'
III. MAJOR TYPES OF FETAL RESEARCH . '
Conceptually, one can distinguish at least the following major categories
of fetal research:
1. Research involving live or dead fetuses
2. Research involving fetuses in utero or outside the uterus
3. Research involving induced abortion or either spontaneous abortion
or spontaneous delivery
4. Research involving previable or viable fetuses*
5. Nontherapeutic or therapeutic (for fetuses) research
6. Research involving various degrees of risk to fetuses: minimal,
moderate or serious.
If one excludes research involving dead fetuses (category 1) and the risk ques-
tion (category 6), one is still left with 16 possible combinations^ of the
remaining categories, i.e., 16 distinct types of fetal research. If one includes
the three levels of risk noted in category 6, this total rises to 48 potential
types of fetal research. (For an attempt to display these various potential
types of fetal research in diagrammatic fashion, see Appendix B.)
There is, however, a more inductive approach which can be adopted in
enumerating the major types of fetal research. One can review reports or survey
articles which have appeared in the medical literature during the past 15 years
to ascertain what kinds of live fetus research have in fact been done. This
survey will be based in part on the literature review performed by Dr. Mahoney's
group.
Chronologically speaking, live fetus research seems to be done most often
at four stages of fetal life: (1) when the fetus is in utero and will remain
in utero for at least one week; (2) when the fetus is in utero and delivery or
induced abortion is anticipated within a few hours or days; (3) during an abor-
tion procedure, i.e., after the procedure has begun but while the maternal- feto-
placenta unit is still intact; and (4) following the completion of abortion,
i.e., after the surgical separation of the fetus from the mother.
From a medical or biological standpoint, one can distinguish the following
major types of live fetus research in the medical literature:
1. Prenatal diagnosis
2. Intrauterine therapy
3. Studies of fetal behavior
4. Nutrition studies
5. Studies of placental transfer
6. Studies of fetal physiology or metabolism
7. Studies of abortion techniques
8. Tissue studies
9. Studies of oxygenation or life prolongation
10. Studies of techniques for facilitating delivery.
Certain of these ten research procedures are likely to be correlated with par-
ticular chronological stages of fetal life.
In the following paragraphs, I shall briefly describe some of the live
fetus research which has been conducted and reported in the scientific litera-
ture of the past 15 years. The studies will be organized according to the four
chronological stages noted above.
1. The Fetus In Utero More Than One Week Prior to Delivery or Abortion
a. Prenatal Diagnosis: The traditional use of x-ray has been supple-
mented by a series of newer techniques, including amniocentesis ,^°
ultrasound,^-' fetoscopy,'^ and fetal blood sampling. ^^
b. Intrauterine Therapy: Intrauterine blood transfusions for Rh
incompatibility have been employed for several years; more recently
attempts have been made to treat adrenogenital syndrome,^* fetal
lung immaturity,'^ and a type of acidemia'^ prenatally.
c. Studies of Fetal Behavior: Most studies seem to concentrate on
fetal response to sound, i7 although some studies investigate the
effect on the fetus of light and other types of stimuli. i^
d. Nutrition Studies: Prospective studies involving animals have
been performed, but few prospective studies on humans have been
done; ^5 a major retrospective study has examined the effect of
the Dutch "hunger winter" of 1944-1945 on fetal development. ^o
8-4
studies of Placental Transfer: Nximerous retrospective studies
have been done concerning the effect on the fetus of drugs
administered to the mother for therapeutic reasons;^-' several pro-
spective studies of placental transfer have been performed prior
to induced abortion, including two rubella vaccine studies. 22 The
prospective studies are performed more than a week prior to induced
abortion, so that sufficient time elapses to allow the effect of
the experimental procedure on the fetus to become apparent.
The Fetus In Utero a Few Hours or Days Prior to Delivery or Abortion
a. Prenatal Diagnosis: Some new techniques of prenatal diagnosis,
for example, fetoscopy, have been tested on fetuses prior to
abortion. 23 -;.^ ^ •
b. Nutrition Studies: In a study entitled "Response to Starvation in
Pregnancy" women scheduled for abortion fasted during an 84-hour
period immediately prior to the abortion procedure.^*
c. Studies of Placental Transfer: In pregnant women nearing the time
of delivery, several studies have investigated placental transfer
of radioisotopes, ethyl alcohol, or steroids. ^^ In cases involving
abortion, numerous studies of placental transfer have been per-
formed.- Most of these studies begin several hours prior to abor-
tion, at which time an agent is administered to the mother intra-
venously. The agent, having crossed the placenta, is recovered
from the fetus during or following the abortion procedure either
by drawing a fetal blood sample or by examining fetal organs.
Specific compounds which have been tested in placental transfer
studies at the time of abortion include: erythromycin and clinda-
mycin,26 125i-giucagon,27 Cortisol, 28 diphenylhydantoin, 29 and
gentamycin. ^°
d. Studies of Abortion Techniques: For the most part, such studies
have concentrated on maternal comfort and safety; ^^ recently one
study has investigated the mechanism by which fetal death is pro-
duced in saline-induced abortion. ■'^
e. Studies of Techniques for Facilitating Delivery: In pregnant
women nearing the time of delivery, numerous studies have been
conducted to test the effect on the fetus of agents which delay
or induce the onset of labor ■'^ and various types of obstetrical
anesthesia, e.g., paracervical block. ^*
The Fetus During the Abortion Procedure, While the Maternal-Feto-
Placental Unit is Intact
Placental Transfer: During abortion by hysterotomy, studies of
placental transfer investigate whether a compound introduced on
8-5
the fetal side of the placenta crosses the placenta and enters the
maternal bloodstream. For example, two studies of fetal circula-
tion and blood volume injected radioactive isotopes into the umbil-
ical vein, then sought to detect the presence of radioactivity in
the mother. 35
b. Studies of Fetal Physiology or Metabolism: In such studies the
attachment of fetus to the placenta and to the mother assures the
continuation of fetal circulation. During hysterotomy procedures
various researchers have investigated blood flow within the fetal
circulatory system ^6 and fetal metabolism of arginine,^' sulfur, ^^
and -'-^^I-glucagon. 3'
The Fetus Outside the Uterus Following Separation from the Mother,
i.e., the Abortus '">
a. Studies of Fetal Physiology or Metabolism: Since the aborted
fetus may continue to live for a period of time following abortion
by hysterotomy or hysterectomy, it is possible to study certain
aspects of fetal physiology even after spontaneous or induced
abortion. One study which involved abortion-hysterectomies per-
fused the pregnant uteri with barium sulfate solution in order to
perform angiographic studies of the circulatory system in the
uterus and the placenta.*^ Another study decapitated eight live
aborted fetuses, perfused the fetal heads through the carotid
arteries, and measured cerebral oxidation of a glucose substitute. *2
b. Tissue or Organ Studies: The removal, or harvesting, of fetal
organs or tissues is frequently the final step in studies of fetal
metabolism which commenced prior to abortion. In some cases such
organs are removed from the still-living organism immediately
following the abortion procedure. Studies which have involved the
retrieval of organs from the live abortus include an investigation
of biosynthesis in the fetal liver and brain*-' and two projects
which examined the enzyme response of the fetal liver.**
c. Studies of Oxygenation or Life Prolongation: Previable aborted
fetuses lack the capacity to breathe and to absorb oxygen through
the lungs. Several investigators have tested the feasibility of
prolonging fetal life by other means of oxygenation. One study
placed fetuses in an immersion chamber and sought to discover
whether "the skin of a fetus immersed in a oxygen-pressured nutri-
ent could be utilized as an organ of absorption and excretion." *5
Another study serially attached several aborted fetuses to an
artificial placenta.**
IV. ETHICAL ISSUES IN FETAL RESEARCH
As the foregoing survey makes clear, "fetal research" is not one but many
things. Several of the studies noted above were clearly therapeutic in intent.
particularly if one considers diagnosis to be a prerequisite of therapy. Other
studies were not done for the benefit of the fetuses involved. The Commission
will no doubt wish to formulate policy for both therapeutic and nontherapeutic
fetal research. However, since it is nontherapeutic research on fetuses which
seems to raise the most serious questions in the public mind, I will concentrate
primary attention on the problem of nontherapeutic fetal research.
The survey of major types of fetal research also indicates that fetal
research involves both fetuses which will come to term and be born and fetuses
which will be, are being, or have been aborted. Here again a limitation is in
order. As the legislation which established the Commission suggests, it is
research which occurs "before or after the induced abortion" of the fetus which
was uppermost in the minds of the lawmakers. I will therefore focus especially
on ethical issues involved in research before, during, or after induced abortion.
Since abortion is generally performed before fetal viability is clearly achieved,
such fetuses will generally be previable or, at most, only possibly viable.
There are few published discussions of the ethical issues involved in live
fetus research.*^ The few documents which do exist reveal that the Commission
is faced with a situation of ethical pluralism. So far as I am able to detect,
there exists no national consensus on the question of fetal research.
In my view, four major positions have emerged on the ethics of research
involving live (not clearly viable) fetuses before, during, or after induced
abortion:
1. Nontherapeutic fetal research should not be done under any circumstances.
2. Nontherapeutic fetal research should be done only to the extent that
such research is permitted on children or on fetuses which will be
carried to term.
3. Greater latitude should be allowed for nontherapeutic fetal research
than for research on children or on fetuses which will be carried to
term. However, certain types of experimental procedures should not
be performed, even in nontherapeutic fetal research.
4. Any type of nontherapeutic fetal research may legitimately be performed.
Position 1 was argued by Monsignor James McHugh in testimony before the
Commission last month. Position 2 was adopted by both the Peel Commission and
the 1973 and 1974 DHEW guidelines with respect to the fetus in utero. Position 3
approximates the regulations of the 1973 DHEW guidelines regarding the abortus
and the 1974 guidelines regarding both the abortus and fetus in utero during an
abortion procedure. Position 4 may have been the view of the Peel Committee on
research involving the live previable abortus; the Report of the Committee is
silent regarding substantive limitations on abortus research.
In this section I shall seek to demonstrate that Position 2 is a reasonable
ethical position. In the succeeding section I shall attempt to show that such a
position could also be translated into a constructive and workable public policy.
8-^7
One can arrive at Position 2 by extrapolating backward from a position on
the ethics of pediatric research. In recent years, some philosophers and ethi-
cists have argued that nontherapeutic research on children who cannot consent
should not be performed under any circumstances.*^ However, Richard McCormick
has presented what seems to me to be a very cogent argument for including chil-
dren in certain kinds of no-risk or low-risk nontherapeutic research. McCormick 's
central thesis is that all members of society owe certain minimal debts to soci-
ety; among these debts is one's obligation to take part in low-risk biomedical
or behavioral research. He concludes that parents should be authorized to con-
sent to a child's taking part in experiments which the child should be willing
to take part in if the child could understand and consent.*'
If one accepts this position on pediatric research, one can easily extend
it to cover the prenatal period in the life of a fetus which will be carried to
term and be born. The parent or parents of such a fetus can be expected to have
the interests of the fetus in view, just as parents of already-born children
normally consider the interests of their offspring. Thus, proxy consent for non-
therapeutic research on a fetus prior to birth is both possible and ethically
consistent with consent for nontherapeutic pediatric research.
In the case of a fetus which will be aborted or has been aborted, the sit-
uation is somewhat more complex. The mother has decided, perhaps for good reason,
that the life of the fetus should be terminated. Because she will not be obliged
to consider the interests of the child on a long-term basis, she cannot give proxy
consent in the same sense as the mother or both parents of an already-born child
or a fetus to be born. There is, in addition, an inherent difficulty in concep-
tualizing what "risk" or "harm" might mean when one is speaking of an organism
which will shortly die at a previable stage of life. I suggest that it is possi-
ble to skirt these difficult problems as well as to be ethically consistent if
one adopts the general rule: Nontherapeutic research procedures which are per-
missible in the case of fetuses which will be carried to term are also permissible
in the case of (a) live fetuses which will be aborted and (b) live fetuses which
have been aborted.
The fundamental presupposition of the position here advocated is that there
is a substantial measure of continuity between previable fetal life and viable
fetal life or pediatric life. This continuity cannot, in my view, be conclu-
sively demonstrated by means of factual arguments. However, a proponent of the
continuity thesis can point to a series of considerations which render the thesis
at least not implausible. It seems clear, for example, that the living previable
fetus has a qualitatively different potential from a living tissue or a living
subhuman animal. ^° One notes, too, that Anglo-American law has displayed a cer-
tain ambivalence vis-a-vis the previable fetus, according to the fetus some, but
not all, of the legal protection enjoyed by children or adults. ^^ It can also be
argued that in form or general appearance the 12- or 16-week-old previable fetus
resembles the viable fetus more closely than it resembles the embryo or blasto-
cyst. Finally, one is struck by both the technology dependence and the somewhat
arbitrary character of the viability watershed: fetuses which twenty years ago
would have been correctly classified as previable are now surviving in neonatal-
care units; today the immaturity of a single organ system, the lungs, constitutes
the major barrier between a 450-gram fetus and viability.
There are strong counterarguments which can be mounted against the
continuity thesis and the ethical position advocated above. I shall briefly
mention and comment on two. It might be argued, first, that the right to have
a previable fetus aborted is firmly established in American law and that the
termination of life is much more harmful to the fetus than any experimental
procedures — even highly invasive procedures--which might be performed upon it.
In response to this argument one would wish to question v/hether abortion and
fetal research are, indeed, analogous questions and whether the moral justifi-
cation of abortion entails, as well, the justification of fetal research. In
the case of abortion there exists a clear conflict between maternal interests
and the developing fetus. The woman alleges a right to be rid of an immediate,
serious threat to her previous pattern of life. This right is now guaranteed
by the law for the stages of pregnancy prior to fetal viability. In the case
of fetal research, however, there is, so far as I can see, no similar clear and
immediate conflict between the previable fetus and society at large or any other
social group. Thus, it would seem that the proponent of highly invasive fetal
research must build an entirely new case for such research rather than being
able to piggyback his or her case on the fact of presumably lethal abortion
procedures .
A second major counterargument to the position taken in this paper is more
consequential in character. This argument can be taken in any of several direc-
tions. It is asserted, for example, that if fetal research proceeds without
limitation, one can expect such research to yield major advances in scientific
knowledge or results of great benefit to all future fetuses and premature
infants. A narrower 'and more limited consequential ist claim is that by per-
forming high-risk safety-studies of new procedures on fetuses which will be or
have been aborted, one can prevent damage to fetuses which will later be born
and who will subsequently bear the stigma of prenatal damage throughout an
entire lifetime.
These are significant arguments and deserve to be taken seriously. There
are, however, several avenues of reply. It may be noted, first, that many of
the benefits promised from fetal research without limitation could also be
achieved by research carried on within the ethical guidelines here proposed.
Second, it can be argued that the positive consequences of fetal research with-
out limitation, desirable as they seem, are not the only consequences which
need to be considered. A comprehensive social-impact statement would take into
account, in addition, the possible dehumanizing effects on investigators of
their performing highly invasive procedures on still-living fetuses. One would
also wish to inquire whether such research would set a precedent for the perfor-
mance of similar procedures on other classes of human organisms — for example, on
newborns who are mortally ill or comatose elderly persons.
The safety-studies argument is perhaps the most difficult one to meet.
Negatively, it seems to me that the potential problems of dehxamanization and
precedent-setting are pertinent to this argument, as well. More positively,
if, as I have advocated, children and fetuses are to be involved in low-risk
nontherapeutic research for the sake of society, then society would seem to
owe such subjects a reciprocal debt. There would inevitably be accidents
resulting from low-risk nontherapeutic or higher-risk therapeutic forms of
8-9
research. In my view, society would have a serious moral obligation to develop
programs of compensation and care for a new class of "disabled veterans "--those
wounded in the battle against disease.
V. RECOMMENDATIONS FOR A NATIONAL POLICY ON FETAL RESEARCH
Policy-making always involves the setting of priorities, and the prior-
ities one chooses reflect the values one wishes to maximize. Thus, there is
always a significant ethical component in the policy-making process.
However, policy making takes into account certain factors which ethics
generally does not. In a pluralistic society it seeks to accommodate a variety
of belief-systems and interests rather than elevating the views of any single
group to the status of national policy. Policy making also attempts to achieve
maximal continuity with some of the generally-accepted principles within the
society. Finally, policy makers, at their best, seek to ensure that national
policies are formulated and expressed in terms that are clearly understandable
to the public at large.
In my view, the Commission is in an ideal position to articulate a clear,
well-reasoned national policy on fetal research which can become the basis for
ongoing discussion and a possible movement toward national consensus. I wish
to recommend that the Commission adopt a policy which emphasizes equality of
treatment or equal protection for all categories of human subjects. More speci-
fically, I would recommend that the Commission adopt a policy which approximates
Position 2 in the foregoing ethical analysis. On the policy level, this recom-
mendation can be stated in terms of three parallel propositions:
1. Nontherapeutic research on children should be permitted, if such
research involves no risk or only minimal risk to the subjects.
2. Nontherapeutic research on fetuses which will be carried to term
should be permitted, if such research involves no risk or only min-
imal risk to the subjects.
3. Nontherapeutic research procedures which are permitted in the case
of fetuses which will be carried to term should also be permitted
in case of (a) live fetuses which will be aborted and (b) live
fetuses which have been aborted.
A policy developed along the lines suggested has numerous advantages, in
my view. I will attempt to list several:
1. It is formal and therefore flexible; it does not prohibit any partic-
ular research procedure but establishes a general test which all pro-
posed procedures would be required to meet.
2. It is a mediating policy, which corresponds to moderate positions on
the spectrum of current ethical opinion regarding fetal research.
8-10
The proposed policy is in continuity with past policy-recommendations
by the Peel Committee and DHEW concerning research involving the fetus
in utero in anticipation of abortion. Like these previous policies,
it protects the woman's rights to change her mind concerning a planned
abortion.
It obviates the need for a definition of viability, since the same
formal guidelines apply to both previable and viable fetuses.
It takes into account the sensibilities of the large numbers of per-
sons who object to highly-invasive research on live aborted fetuses.
Finally, the proposed policy, if adopted, would permit many valuable
types of fetal research to continue. Research involving living tis-
sues from dead fetuses would not be affected in any way by the policy
here proposed and could thus continue unabated. Studies of prenatal
diagnosis, intrauterine therapy, fetal behavior, placental transfer,
fetal physiology or metabolism, oxygenation-techniques , and the facil-
itation of delivery could all be continued, provided that the various
categories of fetuses were treated equally and provided that the non-
therapeutic procedures would involve either no risk or only minimal
risk to the subjects.
In conclusion, I should like to recommend that the Commission devote at
least some attention to one other policy aspect of the fetal-research question,
namely, the development of more adequate protective mechanisms for the pregnant
women who are necessarily involved in fetal research. Bradford Gray's study of
two research projects at Eastern University Hospital seems to demonstrate that
expectant mothers or women seeking abortions are in a particularly vulnerable
position vis-a-vis the health professions and that they are not always ade-
quately informed concerning the research in which their participation is sought.^
I would hope that the Commission's final policy recommendations will include
guidelines for protecting the pregnant woman's right to receive adequate medical
care regardless of her decision concerning possible participation in projects
involving fetal research.
8-11
REFERENCES
1. The estimates suggested here are based primarily on data contained in two
sources. Battaglia, Frederick C. , and Lubchenco, Lula 0., "A Practical
Classification of Newborn Infants by Weight and Gestational Age,"
Journal of Pediatrics 71 (No. 2): 159-163, August 1967. Hellman, Louis M.,
and Pritchard, Jack A., Williams Obstetrics, 14th ed. , New York: Appleton-
Century-Crof ts , 1971, p. 1028. The graph developed by Battaglia and
Lubchenco, based on 1964 data, suggests that both weight and gestational
age may need to be taken into account. (This graph is reproduced in
Appendix A. )
2. Battaglia, Frederick C. , and Lubchenco, Lula 0., op. cit., p. 151.
3. Ibid.
4. Hellman, Louis M. , and Pritchard, Jack A., op. cit., p. 1028. See also
Avery, Mary Ellen, "Considerations on the Definition of Viability,"
New England Journal of Medicine 292 (No. 4): 206-207, 23 January 1975.
5. Office of the Secretary, Department of Health, Education, and Welfare,
Federal Register 39 (No. 105) : 18917 ( § 46.3b) , 30 May 1974.
6. World Medical Association, "Declaration of Helsinki (1964)," reprinted by
Henry Beecher in Research and the Individual : Human Studies, Boston:
Little, Brown, 1970, p. 277. American Medical Association, Ethical
Guidelines for Clinical Investigation (1966), reprinted in Beecher,
Research and the Individual, p. 223.
7. Ibid.
8. As noted above, this category could be further analyzed to include possibly
viable and probably viable fetuses.
9. This figure is based on the following calculation: (1X2X2X2X2).
10. Burton, Barbara K. , Gerby, Albert B., and Nadler, Henry L. , "Present Status
of Intrauterine Diagnosis of Genetic Defects," American Journal of
Obstetrics and Gynecology 118 (No. 5) : 718-746, 1 March 1974.
11. Kohorn , Ernest I., and Kaufman, Michael, "Sonar in the First Trimester of
Pregnancy," Obstetrics and Gynecology 44 (No. 4): 473-483, October 1974.
12. Patrick, J.E., Perry, J.B., and Kinch, R.A.H., "Fetoscopy and Fetal Blood
Sampling: A Percutaneous Approach," American Journal of Obstetrics and
Gynecology 119 (No. 4) : 539-542, 15 June 1974.
REFERENCES (Continued)
13. Hobbins, John C, and Mahoney, Maurice J., "In Utero Diagnosis of Hemo-
globinopathies: Technic for Obtaining Fetal Blood," New England Journal
of Medicine 290 (No. 19): 1065-1067, 9 May 1974.
14. Frasier, S. Douglas; Weiss, Bennett A.; and Horton, Richard, "Amniotic
Fluid Testosterone: Implications for the Prenatal Diagnosis of Con-
genital Adrenal Hyperplasia," Journal of Pediatrics 84 (No. 5) : 738-741,
May 1974.
15. Howie, R.N. , and Liggins , G.C., "Prevention of Respiratory Distress
Syndrome in Premature Infants by Antepartum Glucocorticoid Treatment,"
in Villee, Claude A., et al., eds., i?espiratory Distress Syndrome,
New York: Academic Press, 1973, p. 369-380.
16. Ampola, Mary G. , et al., "In Utero Treatment of Methylmalonia Acidemia
With Vitamin B , Pediatric Research 8 (No. 4) : 387, April 1974.
17. Goodlin, Robert C, and Schmidt, William, "Human Fetal Arousal Levels
as Indicated by Heart Rate Recordings," American Journal of Obstetrics
and Gynecology 114 (No. 5) : 613-621, 1 November 1972.
18. Liley, A.W. , "The Foetus as a Personality," Australian and New Zealand
Journal of Psychiatry 6 (No. 2) : 99-105, June 1972. Sudman, Einar,
"An Embrace-Reflex Observed in a 5 cm Human Fetus," Acta Paediatrica
Scandinavica 62 (No. 5) : 547-549, September 1973.
19. Winick, Myron; Brasel, Jo Anne; and Velasco, Elba G. , "Effects of Prenatal
Nutrition Upon Pregnancy Risk," Clinical Obstetrics and Gynecology 16
(No. 1): 184-198, March 1973.
20. Stein, Zena, and Susser, Mervyn, "The Dutch Famine, 1944-1945, and the
Reproductive Process. I. Effects on Six Indices at Birth," Pediatric
Research 9 (No. 2) : 70-76, February 1975.
21. Carrington, Elsie R. , "Editorial: Relationship of Stilbestrol Exposure
In Utero to Vaginal Lesions in Adolescence," Journal of Pediatrics 85
(No. 2): 295-296, August 1974. Forfar, John 0., and Nelson, Matilda M. ,
"Epidemiology of Drugs Taken by Pregnant Women: Drugs That May Affect
the Fetus Adversely," Clinical Pharmacology and Therapeutics 14 (No. 4,
pt. 2): 632-642, July-August 1973.
22. Bolognese, Ronald J., et al., "Rubella Vaccination During Pregnancy,"
American Journal of Obstetrics and Gynecology 112 (No. 7): 903-907,
1 April 1972. Vaheri, Antti, et al., "Isolation of Attentuated Rubella-
Vaccine Virus From Human Products of Conception and Uterine Cervix,"
New England Journal of Medicine 286 (No. 20): 1071-1074, 18 May 1972.
8-13
REFERENCES (Continued)
23. Chang, Henry, et al., "In Utero Diagnosis of Hemoglobinopathies: Hemo-
globin Synthesis in Fetal Red Cells," New England Journal of Medicine
290 (No. 19) : 1067-1068, 9 May 1974.
24. Gray, Bradford H., Human Subjects in Medical Experimentation: A Socio-
logical Study of the Conduct and Regulation of Clinical Research,
New York: Wiley-Interscience, 1975, p. 56-58.
25. Clavero, Jose A., "Blood Flow in the Intervillous Space and Fetal Blood
Flow, I. Normal Values in Human Pregnancies at Term," American Journal
of Obstetrics and Gynecology 116 (No. 3) : 340-346, 1 June 1973.
Idanpaan-Heikkila, Juhana, et al., "Elimination and Metabolic Effects
of Ethanol in Mother, Fetus, and Newborn Infant," American Journal of
Obstetrics and Gynecology 112 (No. 3): 387-393, 1 February 1972.
Simmer, Hans H., et al., "On the Regulation of Estrogen Production by
Cortisol and ACTH in Human Pregnancy at Term," American Journal of
Obstetrics and Gynecology 119 (No. 3): 283-296, 1 June 1974.
26. Philipson, Agneta; Sabath, L.D.; and Charles, David, "Transplacental
Passage of Erythromycin and Clindamycin," New England Journal of
Medicine 288 (No. 23): 1219-1221, 7 June 1973.
19 5
27. Adam, Peter A.J., et al., "Human Placental Barrier to -^^-^I-glucagon Early
in Gestation," Journal of Clinical Endocrinology and Metabolism 34
(No. 5): 772-782, May 1972.
28. Murphy, Beverly E. Pearson, et al., "Conversion of Maternal Cortisol
to Cortisone During Placental Transfer to the Human Fetus," American
Journal of Obstetrics and Gynecology 118 (No. 4): 538-541, 15 February
1974.
29. Mirkin, Bernard L. , "Diphenylhydantoin : Placental Transfer, Fetal Locali-
zation, Neonatal Metabolism, and Possible Teratogenic Effects," Journal
of Pediatrics 78 (No. 2): 329-337, February 1971.
30. Kauffman, Ralph E.; Morris, John A.; and Azaroff, Daniel L. , "Placental
Transfer and Fetal Urinary Excretion of Gentamicin During Constant Rate
Maternal Infusion," Pediatric Research 9 (No. 2) : 104-107, February 1975.
31. Wentz, Anne C; Burnett, Lonnie C; and King, Theodore M. , "Methodology in
Premature Pregnancy Termination," Obstetrical and Gynecological Survey
28 (No. 1): 2-19, January 1973; 29 (No. 1): 6-42, January 1974.
32. Galen, Robert S., et al., "Fetal Pathology and Mechanism of Fetal Death in
Saline-Induced Abortion: A Study of 143 Gestations and Critical Review
of the Literature," American Journal of Obstetrics and Gynecology 120
(No. 3): 347-355, 1 October 1974.
8-14
REFERENCES (Continued)
33. Nochimson, David J., et al., "The Effects of Ritodrine Hydrochloride on
Uterine Activity and the Cardiovascular System," American Journal of
Obstetrics and Gynecology 118 (No. 4) : 523-528, 15 February 1974.
Gray, Bradford, op. cit. (n. 24), p. 59-65.
34. Freeman, Roger K. , et al., "Fetal Cardiac Response to Paracervical Block
Anesthesia," American Journal of Obstetrics and Gynecology 113 (No. 5):
583-591, 1 July 1972.
35. Rudolph, Abraham M. , et al., "Studies on the Circulation of the Previable
Human Fetus," Pediatric Research 5 (No. 9): 452-465, September 1971.
Morris, John A., et al., "Measurement of Fetoplacental Blood Volume in
the Human Previable Fetus," American Journal of Obstetrics and Gynecology
118 (No. 7): 927-934, 1 April 1974.
36. Rudolph, Abraham M. , et al., op. cit. (n. 35). Morris, J.A. ; Haswell, G.L.;
and Hustead, R.F., "Research in the Human Mid-Trimester Fetus," Obstetrics
and Gynecology 39 (No. 4) : 634-635, April 1972.
37. King, Katherine, et al., "Differing Sensitivity of Human Fetal Receptor
Sites to Arginine-Induced Insulin and Growth Hormone Release," Pediatric
Research 7 (No. 4) : 329, April 1973.
38. Gaull, Gerald; Sturman, John A.; and Raiha, Niels C.R., "Development of
Mammalian Sulfur Metabolism: Absence of Cystathionase in Human Fetal
Tissues," Pediatric Research 6 (No. 6): 538-547, June 1972.
39. Adam, Peter A.J., et al., op cit. (n. 27).
40. This section will not discuss experimentation involving the clearly viable
fetus, which is generally considered to be a newborn infant.
41. Kormano, Martti; Timonen, Henri; and Luukkainen , Tapani; "Microangiographic
Observations on the Uterine and Maternal Placental Vasculature in Early
Human Pregnancy," American Journal of Obstetrics and Gynecology 120
(No. 1): 8013, 1 September 1974.
42. Adam, Peter A.J.; Raiha, Neils; Rabiala, Eeva-Lusa; et al., "Cerebral
Oxidation of Glucose and D-BOH-BUTYRATE by the Isolated Perfused Human
Fetal Head," Pediatric Research 7 (No. 4) : 309, April 1973.
43. Sturman, John A., and Gaull, Gerald E., "Polyamine Biosynthesis in Human
Fetal Liver and Brain," Pediatric Research 8 (No. 4) : 231-237, April 1974.
44. Kirby, Lome; and Hahn , Peter, "Enzyme Response to Prednisolone and Dibutryl
Adenosine 3', 5 ' -Monophosphate in Human Fetal Liver," Pediatric Research 8
(No. 1): 37-41, January 1974. Kirby, Lome; and Hahn, Peter, "Enzyme
Induction in Human Fetal Liver," Pediatric Research 7 (No. 2): 75-81,
February 1973.
REFERENCES (Continued)
45. Goodlin, Robert C, "Cutaneous Respiration in a Fetal Incubator," American
Journal of Obstetrics and Gynecology 85 (No. 5) : 571-579, 1 July 1963.
46. Chamberlain, Geoffrey, "An Artificial Placenta," American Journal of
Obstetrics and Gynecology 100 (No. 5): 615-626, 1 March 1968.
47. The major discussions of ethical issues in fetal research are the following:
a. Report of the Advisory Group, The Use of Fetuses and Fetal Material
for Research, London: Her Majesty's Stationery Office, 1972.
b. Morison, Robert S., and Twiss, Sumner B. , "The Human Fetus as Useful
Research Material," Hastings Center Report 3 (No. 2): 8-10, April 1973.
c. National Institutes of Health, Department of Health, Education, and
Welfare, "Protection of Human Subjects: Policies and Procedures,"
Federal Register 38 (No. 221) : 31738-31749, 16 November 1973.
d. Walters, LeRoy, "Ethical Issues in Experimentation on the Human Fetus,"
Journal of Religious Ethics 2 (No. 1): 33-54, Spring 1974.
e. Reback, Gary L. , "Fetal Experimentation: Moral, Legal, and Medical
Implications," Stanford Law Review 26 (No. 5) : 1191-1207, May 1974.
f. Office of the Secretary, Department of Health, Education, and Welfare,
"Protection of Human Subjects: Proposed Policy," Federal Register 39
(No. 165): 30648-30657, 23 August 1974.
g. Ramsey, Paul, The Ethics of Fetal Research, New Haven: Yale University
Press, 1975.
48. Jonas, Hans, "Philosophical Reflections on Experimenting with Human Subjects,"
Daedalus 98 (No. 2): 219-247, Spring 1969. Ramsey, Paul, "Consent as a
Canon of Loyalty With Special Reference to Children in Medical Investi-
gation," in his The Patient as Person: Explorations in Medical Ethics,
New Haven: Yale University Press, 1970, p. 1-58.
49. McCormick, Richard A., "Proxy Consent in the Experimentation Situation,"
Perspectives in Biology and Medicine 18 (No. 1) : 2-20, Autumn 1974.
50. This point is discussed by Professor Richard Wasserstrom in the preliminary
draft of his paper for the Commission entitled "Ethical Issues Involved
in Experimentation on the Nonviable Human Fetus," February 5, 1975.
51. Louisell, David., "Abortion, the Practice of Medicine and the Due Process of
Law," UCLA Law Review 16 (No. 2): 233ff., February 1969. "Note: The Law
and the Unborn Child: The Legal and Logical Inconsistencies," Notre Dame
Lawyer 46: 349ff . , Winter 1971. The report of Professor Alexander Capron
to the Commission will similarly note that various branches of the law
seem to regard the previable fetus in different ways.
52. Gray, Bradford H. , op. cit. (n. 24), especially chapter 8.
8-16
APPENDIX A
Classification of Newborns by Birth Weight and Gestational Age
and by Neonatal Mortality Risk
5000
4750
4500
4250
4000
3750
3500
3250
3000
2750
2500
2250
2000
1750
1500
1250
1000
750
500
_
- LESS THAN 4% MORTALITY
^
—
goth%
-
_ 4% -25%
MORTALITY
^
10th%
-
/
~ ^
^
7^^
25% ■ 50%
MORTALITY
^,,,^'^
OVER 50%
_ ^y^^ MORTALITY
1 1 1 1 1 1 1 1 1 1 1 1 1 1
1 1
1
1 1 1 1
24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
WEEKS OF GESTATION
LARGE FOR
GESTATIONAL AGE
APPROPRIATE FOR
GESTATIONAL AGE
SMALL FOR
GESTATIONAL AGE
PRE-TERM
TERM
— U POST-TERM A
8-17
APPENDIX B
General Types of Fetal Research
Spontaneous Abortion
or
Delivery
Previable Viable Previable Viable Previable Viable Previable Viable
Nonther. Ther. IMonther. Ther. Nonther. Ther. Nonther. Ther. Nonther. Ther. Nonther. Ther. Nonther. Ther. Nonther. Ther.
Min. Mod. Ser, etc.
ETHICAL ISSUES INVOLVED IN EXPERIMENTATION
ON THE NONVIABLE HUMAN FETUS
Richard Wasserstrom, Ph.D.
RICHARD WASSERSTROM, Ph.D.
Dr. Wasserstrom is presently Professor of Law and
Philosophy at University of California at Los Angeles.
PD 304215-5
Ethical Issues Involved in Experimentation
on the Nonviable Human Fetus
1. THE STATUS OF THE FETUS
I do not believe that the question of the morality of experimentation on
living, nonviable fetuses can be sensibly considered without some attention
being paid at the outset to the question of what kind of an entity a human fetus
is. Although some of the relevant arguments do not depend, even implicitly,
upon an answer to this question, the great majority of them do. That this is
so can be seen, I think, from the fact that the question of experimentation is
a very different one if the fetus is thought to be fundamentally like a piece of
human tissue or organ, e.g., an appendix, than if the fetus is thought to be
fundamentally like a fully developed, adult human being with normal capacities
and abilities.
There are four different views that tend to be held concerning the status
of the human fetus . They are :
(a) That the fetus is in most if not all morally relevant respects like
a fully developed, adult human being. At least two major arguments can be given
in support of this position. The first is a theological argument which fixes
conception as the time at which the entity acquires a soul. And since posses-
sion of a soul is what matters morally and what distinguishes human beings from
other entities, the fetus is properly regarded as like all other persons. The
second argument focuses upon the similarities between a developing fetus and
newly born infant. In briefest form, the argument goes as follows. It is clear
that we regard a newly born infant as like an adult in all morally relevant
respects. Infants as well as adults are regarded as persons who are entitled
to the same sorts of protection, respect, etc. But there are no significant
differences between newly born infants and fetuses which are quite fully devel-
oped and about to be born. What is more, there is no point in the developmental
life of the fetus which can be singled out as the morally significant point at
which to distinguish a fetus not yet at that point from one which has developed
beyond it and hence is now to be regarded as a person. Therefore, fetuses are
properly regarded from the moment of conception as having the same basic status
as an infant. And since infants are properly regarded as having the same basic
status as adults, fetuses should also be so regarded.
Now, of course, on this view abortion, whether before or after viability,
raises enormous moral problems, since it is morally comparable to infanticide
and homicide, generally. And the morality of abortion per se is beyond the
scope of the present inquiry. This view is nonetheless directly relevant, even
on the assumption that abortion prior to viability is morally permissible.
For on this view, for instance, experimentation ex utero upon a nonviable living
9-1
fetus is to be seen as analogous to experimentation upon, say, an adult human
being who is in a coma and who will die within the next few hours. Thus, on
this view, the moral problems of experimentation ex utero would be thought to
be similar to those of experimentation upon adults whose deaths were imminent
and who were themselves unconscious.
(b) That the fetus is in most if not all morally relevant respects like
a piece of tissue or a discrete human organ, e.g., a bunch of hair or a kidney.
The argument in support of this view focuses upon all of the ways in which
fetuses are different from typical adults with typical abilities. In particular,
the absence of an ability to communicate, to act autonomously (morally, as well
as physically), to be aware of one's own existence, and/or to experience sensa-
tions of pain and pleasure would singly and collectively be taken to be suffi-
cient grounds for regarding the fetus as more like an organ growing within the
woman's body than like any other kind of entity. It should be noted, too, that
for our purposes this view includes all those positions which regard the status
of the fetus as changing from something like a human organ to something else
only at or after the moment of viability has been reached. For this inquiry is
concerned only with experimentation upon nonviable fetuses.
On this view there are, I think, virtually no arguments against experi-
mentation ex utero and only a few arguments against experimentation in utero.
Whatever, for example, can properly be done to a severed human organ which still
has certain life capacities (e.g., it is capable of being transplanted into
another human, or it still maintains some of its organ function) can properly
be done to the nonviable fetus ex utero in those few hours before its life func-
tions have ceased.
(c) That the fetus is in most if not all morally relevant respects like
an animal, such as a dog or a monkey. The fetus is, on this view, clearly not
a person, nor is it just a collection of tissue or an organ. It is an entity
which is at most entitled only to the same kind of respect that many (but not
necessarily all) persons think is due to the "higher" animals. It is wrong to
inflict needless cruelty on animals — perhaps because they do suffer or perhaps
because of what this reveals about the character of the human imposing the
cruelty. And fetuses are, basically, in the same class.
On this view, too, there are comparatively few worries about experimenta-
tion ex utero on nonviable fetuses. At most, the worries are of the same sort
that apply to experimentation upon living animals. For the most part, it is
proper to regard them as objects to be controlled, altered, killed, or otherwise
used for the benefit of humans--subject only to concerns relating to the inflic-
tion of needless and perhaps intentional pain and suffering upon the entities
being experimented upon, and (in the case of those higher animals we most iden-
tify with) to prohibitions upon their consumption as food.
(d) That the fetus is in a distinctive, relatively unique moral category,
in which its status is close to but not identical with that of a typical adult.
On this view the status of the fetus is both different from and superior to that
of the "higher" animals. It is, perhaps, closest to the status of the newly
born infant in a culture in which infanticide is regarded as a very different
9-2
activity from murder or to the status of the insane, the mentally defective or
slaves — again in cultures which see them as less than persons but as clearly
superior to animals. The case for regarding fetuses as belonging to a special,
discrete class of entities rests, I think, largely on the fetus' potential to
become in the usual case a fully developed adult human being. Conceding that
the fetus is significantly different from an adult in respect to such things as
its present capacity to act autonomously, to experience self-consciousness, and
perhaps even to experience pain, this view emphasizes the distinctiveness of the
human fetus as the entity capable in the ordinary course of events of becoming
a fully developed person. This view sees the value of human life in the things
of genuine value or worth that persons are capable of producing, creating,
enjoying, and being, e.g., works of art, interpersonal relations of love, trust
and benevolence, and scientific and humanistic inquiries and reflections. Cor-
respondingly, it sees the distinctive value of the fetus as being alone the kind
of entity that can someday produce, create, enjoy and be these things of genuine
value and worth.
It is, I think, especially important to notice the implications of this
view for the morality of experimentation upon nonviable fetuses ex utero. For
it is the nonviability of the fetus that goes, I believe, a long way toward
making experimentation a substantially less troublesome act than it would other-
wise be. That is to say, it is evident, I think, that on this view abortion is
a morally worrisome act because it involves the destruction of an entity that
possesses the potential to produce and be things of the highest value. However,
if an abortion has been performed and if the fetus is still nonviable, then
experimentation upon the fetus in no way affects the fetus' ability, or lack
thereof, ever to realize any of its existing potential. On this view especially,
abortion, not experimentation upon the nonviable fetus is the fundamental, morally
problematic activity.
2. SPECIFIC ISSUES RELATING TO EXPERIMENTATION EX UTERO
I propose now, within the context of the discussion in section 1, to turn
to an examination of what seem to me to be the specific issues that arise in
thinking about the morality of experimentation upon nonviable, living, human
fetuses ex utero. The examination will be divided into four parts: (a) an
enumeration and analysis of the arguments against experimentation; (b) an enu-
meration and analysis of the arguments in favor of experimentation; (c) an enu-
meration and discussion of some specific problems that arise in respect to the
question of consent; and (d) a statement of my own view about the permissibility
of experimentation.
A. The Major Arguments Against Experimentation Upon Nonviable, Living,
Human Fetuses Ex Utero. The arguments can be divided in a rough fashion into
two groups: those that, on the one hand, oppose experimentation because of the
possible, deleterious consequences that are thought to follow from the legiti-
mization of such a practice; and those that, on the other hand, oppose experi-
mentation because of some feature of the situation that is seen to be itself
wrong or improper. I begin with the former collection of arguments — those that
concentrate upon the possible, deleterious consequences.
9-3
(1) Possible, Deleterious Consequences of Permitting a Practice of
Fetal Experimentation. One general argument here is that if such a practice is
permitted and well publicized then individuals and, in some related sense, the
society will become less sensitive to values and claims which are entitled to
the greatest respect. Thus, one specific version of this general line of attack
is the argument that individuals will become less sensitive than they ought to
be to the value of human life. Another specific claim is that indrvIBuais will
become less sensitive than they ought to be to the rights and needs of persons
who are, for one reason or other, incapable of looking after themselves, e.g.,
infants, the aged, and the seriously ill or retarded. Still a third, related
worry is that individuals will become less sensitive than they ought to be to
the claims of those persons whose deaths are reasonably thought to be certain
and imminent, e.g., persons in the last stages of terminal illnesses. And a
fourth, consequential concern is that individuals will become less sensitive
than they ought to be to the rights of persons not to be the unwilling subjects
of experimentation.
I think one thing that is of interest about all four of these arguments is
that they can retain some if not all of their force irrespective of what is
thought in fact to be the correct view about the kind of entity a fetus is. That
is to say, consider the claim that permitting fetal research may lead individuals
to become less sensitive than they ought to be to the rights and needs of persons
who are, for one reason or another, incapable of looking after themselves. Even
someone who is convinced that a fetus is basically like a human organ might
nonetheless legitimately worry about the inferences that individuals would mis-
takenly draw from the permissibility of a practice of fetal research. As long
as it is reasonable to believe that persons, in any significant number, might
mistakenly suppose that the principle which justified fetal experimentation was
a principle which justified experimentation upon any entity that was incapable
of keeping itself alive without substantial human assistance, this is a deleteri-
ous consequence of a practice of fetal experimenation which would have to be
taken into account. Of course, the more one thinks that a fetus is like other
persons in most significant respects, the more one is also apt to think that
individuals generally may confuse the case of the fetus with the case of those
other entities whose claims to morally more sensitive treatment are nonetheless
distinguishable.
A rather different consequential argument goes like this. Once it becomes
permissible for experiments to be done on living, nonviable fetuses, such fetuses
will come to be regarded as extremely useful in medical research. The increased
demand for fetuses within the scientific community will lead to the creation of
a variety of subtle as well as obvious incentives for persons both to have abor-
tions and to have them in such a way that the fetus can be a useful object of
experimentation. And this is undesirable for several reasons. To begin with,
unless it is the case that abortion is a morally unproblematic action, it is
wrong to develop a social practice which will encourage persons to have abortions.
In addition, the fact that fetuses are useful objects of experimentation might
lead members of the scientific and medical community unconsciously to distort
or alter their views of when persons should have abortions. Doctors might in
this way take into account nonmedical reasons for advising patients to have
abortions. And, finally, there is always the danger that the pressures and
inducements would operate unequally throughout the society — persons from a low
socioeconomic status would be the ones who were more likely to be attracted by
the incentives and subjected to the pressures.
Still a third argument, which may or may not be consequential, points to
the fact that many individuals will experience revulsion and will be in psychic
turmoil when they learn of fetuses being treated in this way, i.e., as objects
of experimentation. The revulsion and turmoil are comparable, although less
universal, than that encountered at the thought of such things as cannibalism,
and the desecration of graves. If a large number of persons respond this way,
then one argument against experimenation is that it will substantially impair
social peace and harmony. Because they care so strongly, they will be led to
act antagonistically toward the source of their discomfort. In addition, even
if the numbers are not large, the severe quality of their reactions may justify
prohibition simply on the ground that the gains of experimentation do not over-
balance the pain and discomfort experienced by those who are so affected.
(2) Arguments for the Intrinsic or Direct Wrongness of Fetal
Experimentation. I can identify approximately a half-dozen arguments that in
some direct, nonconsequential way call into question the morality of fetal
experimentation upon nonviable, living fetuses. More so than in the case of
the consequential arguments, the force of these arguments often depends upon
the status that it is thought ought properly be accorded the fetus.
The first two arguments relate to the principle involved in fetal experi-
mentation. One such argument is this: To permit fetal experimentation is at
least to commit oneself to the principle that it is permissible to perform com-
parable experiments upon any living person, provided only that we have gooS
reason to believe that the person will die very soon, i.e., within a few hours,
anyway. But since it is surely wrong to experiment on persons just because
they will die anyway within a few hours, experimentation on nonviable, living
fetuses lacks a coherent principle of support.
The other argument is similar: To permit fetal experimentation is to
commit oneself to the principle that it is permissible to perform comparable
experiments on all living persons, provided only that they are no longer con-
scious and will not regain their consciousness before they die. But since it
is surely wrong to experiment on all such persons, experimentation on nonviable
living fetuses lacks a coherent principle of support.
In both cases it is, I think, clear that the force of the argument depends
upon the claim that fetuses are sufficiently like other human persons so that
there are no plausible, reasonably persuasive grounds upon which to distinguish
the way in which the fetus is treated from the way in which other persons, e.g.,
the terminally ill or the unconscious, could also properly be treated. The
argument appeals both to a claim that it would be wrong to treat other persons
in this way and to a claim that the case of fetal experimentation cannot be
readily or convincingly distinguished.
A third argument concerns the concept of viability. It is this: The
concept of viability is anything but a precise one, even within medical science.
9-5
It is fundamentally the idea that the fewer the number of weeks of gestation
the less likely it is that any medical means presently exist by which the fetus
could be kept alive until it could function without artificial support. The
problem is not just one of imaginary, theoretical possibilites. Given the
present state of medical technology there will at best be a range within which
it is relatively likely or unlikely that the fetus could be kept alive, i.e.,
is viable. This means that it is not the case that all fetuses classified as
nonviable for purposes of experimentation would necessarily have died no matter
what steps had been taken to try to maintain their lives. Now it is clear
that once a fetus is viable it is wrong to experiment upon it in ways that are
potentially harmful to it. But if this is so, then in some significant number
of cases comparable experiments will be performed on fetuses classified "non-
viable" but perhaps really viable.
The plausibility of this argument depends both upon the claim that dele-
terious experimentation upon viable fetuses would be wrong and upon the claim
that a significant number of moderately developed fetuses determined to be
nonviable might in fact have proved to have been viable, if they had not been
the subjects of experimentation.
A fourth argument is this: We believe that fetal experiments which
directly terminate either respiration or heartbeat are wrong; see, e.g., "Pro-
tection of Human Subjects: Policies and Procedures," DHEW. But there is no
real difference between that and engaging in experiments in which the risk of
terminating respiration or heartbeat is substantially increased. Hence, if the
former is wrong, the latter must be too.
I think this argument is surely correct in its insistence upon the absence
of any convincing way to distinguish experiments which directly terminate either
respiration or heartbeat from those that increase the risk of termination signi-
ficantly. What remains the open question, however, is whether there is any good
moral reason to regard as improper experiments which directly terminate the
respiration or heartbeat of a nonviable fetus.
The fifth argument concerns the general question of the relationship
between means and ends in morality. Let it be conceded, so this argument goes,
that good ends, e.g., the prevention of premature births, are sought to be
achieved through this kind of fetal experimentation. Nonetheless, if the means
used to achieve that end are morally unacceptable, it is wrong to seek that end
in this way. Hence the pursuit of a good end cannot justify experimentation on
nonviable fetuses.
This argument leaves two questions unanswered. To begin with, the argu-
ment assumes rather than explains the immorality of this kind of experimentation
on nonviable fetuses. Unless independent grounds are offered to establish the
impropriety of such experiments, the argument is at best hypothetical: if such
grounds exist, they cannot be overridden by the worth of the end that is sought.
In addition, the argument assumes both the possibility of separating clearly
means from ends and the wrongness of using bad means to achieve a good end.
Neither assumption seems to me to be unproblematic, and both would require dis-
cussion and analysis of a sort which lies beyond the scope of this inquiry.
9-6
The remaining argument relates especially to those experiments which pro-
long the life of the nonviable fetus, but also to some experiments which do not.
The argument is that all experiments which cause the fetus more pain than it
would otherwise experience are bad just in virtue of this fact. I do think that
it always counts against the doing of an action that it increases the amount of
pain in the world, and it always counts substantially against the doing of an
action that it increases the amount of pain experienced by human beings. Thus,
this argument would, I think, be a relevant argument if it were the case that it
was reasonable to think that the nonviable fetus had the present capacity to
experience pain, even in the sense, say that we think animals like dogs and
horses do. And the argument would be an especially important one if it were the
case that it was reasonable to think that the nonviable fetus possessed the pres-
ent capacity to experience pain in roughly the same sense or way in which fully
developed persons do.
B. The Major Arguments in Favor of the Permissibility of Experimentation
Upon Nonviable, Living Fetuses Ex Utero. As has already been indicated, some of
the arguments depend quite directly upon what view is held concerning the status
of the fetus, and others do not. More specifically, if the nonviable fetus is
properly regarded as basically a human organ or piece of tissue, little if any-
thing more than scientific curiosity is needed to justify experimentation. In
the same way, if the nonviable fetus is properly regarded as basically like a
higher animal, e.g., a monkey, genuine scientific curiosity coupled with the
avoidance of unnecessary suffering, if any, is all that is required.
The chief argument that applies, even if the nonviable fetus enjoys some
other, more significant status, consists in a threefold claim. First, things
of great usefulness vis-a-vis the preservation and improvement of human lives
can be learned from these experiments. Second, things of great usefulness
vis-a-vis the preservation and improvement of human lives can only be learned
from these experiments. And third, to describe the fetus as nonviable is to
concede that no matter what is done, all signs of life will disappear from the
fetus within a very short period of time, i.e., not more than four or five hours.
Thus, it is claimed, the conjunction of utility, need and inevitability combine
to establish the legitimacy of this kind of experimentation, irrespective of
the status of the fetus.
One important objection that this argument must confront is this: If
experimentation is justifiable under these conditions, then it is also justi-
fiable in the case of a person who is unconscious, and who will die soon with-
out regaining consciousness, e.g., because he or she is in the last stages of a
terminal illness. But because it is wrong to experiment on adults who are in
this state, it cannot consistently be maintained that it is right to experiment
on the fetus.
At least two responses are possible. First, it might be argued that
fetuses are just in a different class from adults. To be sure, there may not
be anything intrinsically wrong with experimenting on an adult in the circum-
stances just described. However, to permit experimentation would be an unwise
exception to the doctrine of the sanctity of human life. Because fetuses are
perceived to be different entities from fully developed persons, to permit
experimentation on them is not to create the same kind of dangerous exception.
Second, it might be argued that the two cases are distinguishable in that
there is no analogue to the concept of nonviabiiity in the case of the adult.
That is to say, medical science cannot identify with confidence those cases in
which an individual will die soon without regaining consciousness, in the same
way in which it can identify with confidence those fetuses that are not yet
viable.
There is one other argument in favor of experimentation that is worth
noting. It is that if there is no good, moral reason to prohibit experimenta-
tion, then a decision to prohibit it encourages the practice of making social
decisions on nonrational if not irrational grounds. And this is a generally
unwise thing to do. That is to say, it might be maintained that experimentation
should be prohibited just because it seems wrong or offensive even though no one
can give a plausible account of why it ought to be so regarded. This argument
is an answer to that way of proceeding. It is an argument for the importance of
restricting scientific inquiry only if there are good reasons and not, for exam-
ple, irrational or superstitious objections to the investigations.
C. The Issue of Consent. There is a general problem of consent that
arises: namely, that the fetus will not have consented to anything. The ques-
tion is whether that should make a difference. It might be argued, of course,
that an experiment is always improper unless the subject of the experiment
agrees or consents to being a subject. Since the fetus did not consent to being
a subject, any experimentation upon the fetus is improper. The difficulty with
this position is that there is no obvious way to decide whether the principle
should apply to entities who are not capable of consenting, and if so, to which
kinds of entities. It will depend upon the view that is taken of the status of
the fetus, and the possible answers will parallel those discussed above in the
first part of the paper. If the fetus is a person, then consent will be
required (but so, a fortiori, should consent have been required for the abor-
tion) , etc. I conclude, therefore, that no new general problem is raised by
the absence of the consent of the fetus to being the subject of experimentation.
There is, however, a related issue that is worth mentioning. It is pos-
sible, I think, to hold a variety of views about the status of the fetus and
still believe that the mother, or perhaps both parents, have a legitimate claim
to have their consent secured before any fetal experimentation occurs. The
justification cannot, of course, be that to require the consent of the parents
will protect the fetus from harm. That is because having elected to terminate
the pregnancy the parents are already in a nontraditional, atypical relationship
vis-a-vis the offspring. So it cannot be that the consent of the parents should
be required as a means of protecting the fetus, or looking after its interest.
Still, the parents may have sensibilities, attitudes, etc., that are deserving
of respect — sensibilities, etc., that correspond to those of living persons toward
a deceased relative. It is not exactly that they "own" the deceased, but that
9-8
they do have a legitimate claim to decide how the body of the deceased shall be
dealt with. In the same way, I think, parents of an aborted fetus could still
quite often see themselves as being in a similar relationship to the fetus, such
that they would feel themselves injured in serious ways were the fetus to become
the subject of experimentation without their agreement. For this reason, I
believe that the consent of the mother (in the case of an unmarried woman) or of
both parents to any experimentation should be required before the abortion occurs,
and that the nature of the proposed experiments should be explained carefully
and fully to them.
D. Recommendations Concerning Experimentation Ex Utero. My own view is
that the fetus enjoys the kind of unique moral status described in section 1(d)
above. Hence, abortion on demand seems to me to be a very troublesome moral
issue. If the morality of the abortion is not in question, however, then I
somewhat uncertainly conclude that experimentation ex utero may be permissible
provided the following conditions are satisfied:
(1) The consent of the mother (if unmarried) or of both parents should
be procured before the abortion, and the experiments clearly described to those
whose consent is required.
(2) It should be determined by a body independent of those proposing
the experiments that the experiments can reasonably be expected to yield impor-
tant information or knowledge concerning the prevention of harm or the treatment
of illness in other human beings. That same body should also determine that the
desired information or knowledge is not reasonably obtainable in other ways.
(3) Those medical persons who counsel a woman concerning abortion
and secure the requisite consent should not be the same persons — or affiliated
directly with those persons--who will be involved in the experimentation.
(4) No experiments should be permitted on an aborted fetus which
might in fact be viable, given the state of present medical ability.
3. SPECIFIC ISSUES RELATING TO EXPERIMENTATION IN UTERO
The cases that seem to me to be problematic are those in which there is a
reasonable risk that the experiment will be harmful to the fetus and in which
the experiments are not undertaken in order to benefit the particular fetus.
Much of what has been said about experimentation ex utero applies to these cases
as well. In addition, however, there are several new arguments that are rele-
vant only in these cases.
The most significant one against experimentation in utero is that the
fetus' nonviability has not yet been established in the same way in which it has
been in the case of experimentation ex utero. That is to say, in the latter case,
the abortion has already occurred and ex hypothesis the fetus cannot survive no
matter what is done. In the former case, however, the abortion has yet to take
place, and until it does there is always the genuine possibility that the mother
may change her mind and decide not to have the abortion at all.
Because this is so, the possibility of intervening injury resulting from
the experimentation creates the following dilemma. On the one hand, if the
mother changes her mind and decides not to have the abortion, the chances have
thereby been increased that she will give birth to a child who is unnecessarily
injured. It seems unfair to the child, the society, and the parents to bring
into the world a child with defects or disabilities that could have been pre-
vented.
On the other hand, if the mother is required to proceed with the abortion
because the experiments have been undertaken, the state is regarding the origi-
nal consent to the abortion as irrevocable and it is, in essence, requiring her
to submit to the abortion against her will.
There is, in addition, a related matter. The fact that potentially
damaging experiments have been performed on the fetus will itself constitute
an added inducement to the mother to go through with the abortion and not change
her mind. That is to say, experimentation itself makes abortion more likely
because the belief that the fetus has been injured will make the mother less
likely to change her mind. If abortion is viewed as the kind of serious act
that ought not be "artificially" encouraged, then the intervening experimentation
may be objected to as just such an "artificial" inducement or encouragement to
stay with the original decision to have the abortion.
For the above (and other) reasons I think it important that the decision
to have an abortion be kept easily revocable, up until the time of the abortion.
And for this reason I do not think that any experiments in utero should be per-
mitted, where those experiments involve a substantial risk of injury to the
fetus.
10
FETAL EXPERIMENTATION:
MORAL ISSUES AND INSTITUTIONAL CONTROLS
Stephen Toulmin, Ph.D.
STEPHEN E. TOULMIIM, Ph.D.
Dr. Toulmin is presently Professor of Social Thought
and Philosophy at the University of Chicago.
PD 304083-5 (7)
Fetal Experimentation:
IVIoral Issues and Institutional Controls
I. INTRODUCTION . .
This paper surveys concisely the range of views available in the current
literature, and in the preliminary papers available to the Commission up to
March 1, 1975, about the moral admissibility of fetal experimentation, and
about the institutional controls that appear desirable in present circumstances
to protect the legitimate rights and interests of those affected by such experi-
mentation. It is designedly a selective, not an exhaustive survey. It focuses
particularly on those questions that most directly relate to the practical tasks
of the Commission, in recommending a policy and guidelines for the public
licensing and control of fetal experimentation; and it considers the fundamental
theoretical issues involved only more briefly, in an appendix.
The reasons for handling the issues in this way are not merely pragmatic.
They reflect also the fact that the doctrinal commitments and philosophical
standpoints of the different participants in this discussion turn out, in the
event, to have had less influence than may have been expected on the practical
recommendations they are prepared to support. To be sure, the recommendations
actually offered cover the whole spectrum from an outright ban on nontherapeutic
fetal experimentation to a policy of complete freedom for biomedical research
on fetal material. But a substantial moderate consensus emerges, which stops
short of an outright ban, and advocates a system of social controls carefully
designed to limit the scope, and prevent the abuse, of fetal experimentation.
This consensus cuts sharply across doctrinal lines. (It proves compatible, for
instance, both with support of the thesis that a fetus is a "person," and with
rejection of that thesis.) While analyzing the main lines of difference between
the various positions advanced in the course of the debate, accordingly, the
present paper will concentrate on exploring the nature, basis and implications
of this moderate position, and on carrying further the questions it raises into
some additional areas that seem to me have been neglected in the discussion to
date .
The additional areas of discussion taken up here arise out of the social
context of the current controversies surrounding the subject of fetal experi-
mentation. Although the nature of this context is implicitly acknowledged in
several of the papers before the Commission — e.g., in LeRoy Walters' discussion
of the dangers of brutalization — it is worth bringing the delicate issues it
raises into the open here. Three groups of basic social issues are involved:
all of these reflect a certain loss of confidence, on the part of the public at
large, in the absolute commitment of medical practitioners and their contemporary
allies, the biomedical research scientists, to the immediate personal welfare of
each individual patient.
10-1
(1) There is a widespread sense that the medical advice given by atten-
dant physicians to their patients may in some cases be directed less towards
the individual's personal benefit than towards some research project to which
the physician is directly or indirectly committed, and in which the patient
becomes unwittingly involved.
(2) There is a suspicion that biomedical research scientists are insuffi-
ciently hesitant to perform experiments on human subjects or human tissues, and
that their experiments are, in some cases, motivated as much out of a concern
for personal achievement or the satisfaction of intellectual curiosity as from
the desire to improve therapeutic techniques.
(3) There is a fear that the burden of human experimentation in general,
and more particularly fetal experimentation, is liable to fall unduly on those
groups in the population that are in present circumstances least likely to
benefit from any therapeutic advances that result.
The point of making these fears and concerns explicit here is not to
endorse them, or to suggest that they are necessarily well-founded. It is
merely to put it on record that they exist; that their existence and currency
are relevant to the political decisions which led to the Commission's establish-
ment, and influenced its terms of reference; and--most important — that they give
rise to legitimate interests, which have a moral claim to protection in the
Commission's recommendations. I shall be discussing the topic in more detail
later. At this point, let me just add two brief side comments. First, it was
inevitable that the shift in medical attention characteristic of the 1950s and
1960s, away from general practice and individual health care and towards the
newly renamed "biomedical sciences," should eventually have occasioned some
critical social and political questions about the physician's contemporary role
and responsibilities; and it is no surprise, given the particular delicacy of
the problems intrinsically involved, that these questions should have arisen
with particular force in connection with fetal experimentation. Second, we
must take care not to assume — erroneously — that this loss of confidence is con-
fined to the ignorant, the prejudiced and the ill-motivated. Anybody who was
present in person at the recent public discussion on human experimentation
organized by the National Academy of Sciences, or who received detailed first-
hand reports on it, will know otherwise.
The discussion that follows deals, in succession, with:
(1) The basic question, whether fetal experimentation is morally admis-
sible at all.
(2) The issues raised by the moderate position, which would permit a
limited program of nontherapeutic fetal experimentation, subject to carefully-
designed controls — specifically, with the practical balance to be struck between
risks and benefits, in deciding what fetal research should be permitted, and
with the consent procedures called for in order to protect all those having
legitimate rights and interests.
10-2
(3) An appendix, with the underlying questions, having to do (a) with the
dispute about "personhood" and related concepts — life, human potential, sentience,
quickening, and also "viability," in at least two senses of a highly ambiguous
term — and (b) with the need to improve our understanding of the psychology of
pregnancy — notably of a woman's changing psychological investment in her issue
during the course of pregnancy, as affecting the "rights" she can properly claim
over the handling and disposal of that issue, when it is lost through abortion
or miscarriage at different stages in the pregnancy.
II. THE MORAL ADMISSIBILITY OR INADMISSIBILITY OF NONTHERAPEUTIC FETAL
EXPERIMENTATION
Before there is any question of discussing the practical limits or controls
needed in any policy for a restricted program of fetal experimentation, a prior
ethical question must be faced:
Is the use of experimental procedures on a human fetus, or on fetal
tissues and organs, morally admissible at all in situations where
those procedures are "nontherapeutic," i.e., not immediately directed
to the individual medical benefit of the affected fetus or mother?
Papers before the Commission give answers to this prior question that range all
the way from advocating a total ban on all nontherapeutic fetal experimentation,
by way of various carefully-qualified middle-of-the-road positions, to the view
that any such research is morally admissible, provided only that it aims at
improved medical knowledge. If the former view is accepted the question of
practical restrictions and controls does not (of course) even arise. If the
latter view is accepted there would be no need for any special controls over
fetal research, beyond those that apply to all human experimentation. So, our
first task here will be to look at the arguments advanced in support of these
two extreme positions.
The Case Against Special Controls
The case for the most liberal position towards fetal experimentation is
argued by Joseph Fletcher. As I understand the case, Fletcher accepts an over-
riding moral claim in favor of the pursuit of biomedical knowledge, and sees
nothing in the obstetric situations characteristic of fetal research to limit
the scope of that claim, beyond a requirement of maternal consent in the case
of fetuses (whether in utero or ex utero) which are still alive:
"In fetal research, whether with live or lifeless fetuses, what we
are after is the ability to save life and lift its quality. Our goal
is useful medical knowledge .... We must be delivered from the
kind of ethics which let 'principles' . . . nullify useful know-how
in medicine's effort to save and improve life."
The chief thrust of Fletcher's argument is directed against those who would pro-
ject such a liberal policy, and would place restrictions on biomedical research
10-3
in the name of general or universal "principles." Their argument he construes
as part of a political campaign to impose on medical scientists, against their
own feelings and better judgments, limitations that are required only by adher-
ents to a "doctrinaire and rule-oriented" system of ethics. In reply, Fletcher
pleads for a "pragmatic and value-oriented" approach to the issues in dispute,
based not on a "categorically rigid" insistence on hard-and-fast rules or prin-
ciples, but on a readiness to consider problems "situationally" or case by case:
an approach that will be "nondogmatic, flexible, particularized, value-oriented."
He is evidently confident that, in all cases involving a "tension between life-
saving research . . . and prohibitions on fetal research," such a situational
approach will certainly lead us to come down on the side of medical science.
With all respect, I cannot agree that this conclusion follows, even on
Joseph Fletcher's own grounds. The distinction between "rule-oriented dogmatism"
and "value-oriented pragmatism" is not (as I understand it) a distinction that
cuts between rival systems of ethics. Rather, it cuts between alternative ways
in which any ethical system can be applied to actual cases. Whatever consider-
ations are appealed to as morally relevant to a case in question, that is, they
can be advanced in either a dogmatic or a pragmatic spirit; but the task of
demonstrating that specific considerations are or are not morally relevant to a
particular case is a separate matter. As a result, the case for restricting
fetal research is not met by merely pointing out that advocates of restriction
frequently present their case in a dogmatic or absolutist spirit. On the con-
trary, it must be shown that the specific considerations appealed to by the
restrictionists lack the moral relevance to the fetal research situation that
they claim. Otherwise, the case for restriction can equally well be advanced
in a "situational" manner, and in a "pragmatic and value-oriented" spirit.
(As I read it, this is just what Sissela Bok does in her paper.)
In my view, Joseph Fletcher has not succeeded in demonstrating the impos-
sibility of arguing a case for limitations and controls in precisely such
"situational" terms. The problem for his approach is that "situations" are not
self-describing. With the most flexible and value-oriented spirit in the world,
we might still acknowledge (e.g.) that a woman has a genuine moral stake in the
disposal of her own aborted issue, even after it is unquestionably dead, and so
regard Fletcher's guidelines for fetal research as disregarding her legitimate
interest. Different characterizations of the fetal research situation can thus
lead to different moral conclusions about the admissibility of such research,
and Fletcher's argument comes to an end (it seems to me) before the operative
issues have been addressed, whether in a pragmatic spirit or any other.
To put the point in Fletcher's own vocabulary, the Commission's terms of
reference call for guidance, precisely, over the questions (1) which of the
alternative particularized descriptions of the fetal research situation properly
balances up all the values and benefits that constitute authentically relevant
moral features of that situation; and (2) on what conditions the categorical
present claims, benefits and interests of individuals may properly be set aside
in favor of hypothetical future benefits to "science" or "mankind" in general.
The Case For a Total Ban
At the opposite end of the spectrum is the conclusion that fetal experi-
mentation is justifiable only where its aim is immediately therapeutic, and so
should be "limited to procedures which have as their aim the enhancement of the
life-systems of the f etuses"--i .e . , the particular fetuses which are being
experimented on, not fetuses in general. On this view, all nontherapeutic fetal
experimentation should be banned as morally inadmissible. All of the arguments
advanced in support of such a ban concede that the fetus is — at any rate, after
a certain point in pregnancy — a creature of a kind that is entitled to primary
rights, but otherwise they take two rather different forms. There are those
that deny that any third parties can have the right to give proxy consent for
such experimentation on behalf of the fetus, and there are those that deny the
medical scientist's right to pry into "the secrets of the Almighty," or to
"compromise the dignity" of present human life for the hypothetical benefit of
future human beings. Both Paul Ramsey and Seymour Siegel advance arguments of
the former type. Siegel alone puts major weight on the latter; though LeRoy
Walters also argues, more generally, that there are genuine risks of brutal-
ization involved in permitting exceptions to the rule that hypothetical and
general future benefits may not be sought at the price of categorical and
particular present suffering.
Let me cite Seymour Siegel 's draft paper first:
"The burden of, proof is on those who wish to subordinate the life of
an individual presently before us for the interests of what might
come later. In other words experimental procedures for 'the good of
medicine' are not automatically legitimated because someone in the
future might benefit. Our concern primarily should be for the per-
son or persons before us now. The rest of what is called in the
Talmudic literature 'the secrets of the Almighty.' These reflections
do not, of course, preclude the scientist's search. It is intended
merely to circumscribe it."
When considered in the light of its historical origin, the Talmudic appeal to
the sanctity of Divine "secrets," together with Siegel 's call for caution in
the face of "the indeterminacy of the future," must indeed be understood — on the
face of the words — as precluding not just nontherapeutic fetal experimentation,
but biomedical research of all kinds. In this respect, Siegel 's preliminary
argument, like Fletcher's, does not seem to me sufficiently fine-grained, as it
stands. Is fetal research in his view on all fours with all nontherapeutic
biomedical research? Or are there special limitations on fetal, as contrasted
with later medical experimentation? If the latter is the case, then what are
the morally relevant considerations distinguishing the two classes of research?
Do these have predominantly to do with the problem of consent, as in Ramsey's
argument? Or are there other considerations? It would be helpful if he could
spell out more exactly what the crucial moral factors are, on his account.
What guidance does Siegel give us, in fact, about the conditions on which
fetal research might have been morally admissible, despite the general burden
of proof against incautious research projects? As I read his view, adult
10-5
patients of sound mind do have the right to consent to nontherapeutic experi-
mentation on their own bodies since the act of giving informed consent protects
their human dignity from compromise. If that is the crucial factor, then
Siegel's case for a ban on nontherapeutic fetal research becomes the same as
Ramsey's. Both men agree that the problem of obtaining adequate fetal consent
to such experimentation is insuperable, and so conclude that fetal experimen-
tation is admissible only if its aims are directly therapeutic for the particu-
lar fetus under examination.
Taking all the available literature together, then, it is clear that the
central arguments for or against a total ban on nontherapeutic fetal research
are those which turn on the admissibility of proxy consent, by the mother, the
father or other third parties. These arguments will, of course, be fully con-
vincing either way only to those who accept the notion that the fetus itself
can have morally relevant "claims" or "interests" in its own right. (The denial
of primary rights to the "previable" fetus entails that no question of proxy
consent can arise; so that, on this alternative position, only the mother's own
primary consent can come up for question.) Over this central issue, the cases
presented by Paul Ramsey for, and Father Richard McCormick against a total ban
carry particular weight.
Rather than attempting to condense their close arguments still further,
at the price of distorting them, let me simply recall the precise point at which
the two men part company. Granted that it is out of the question for the fetus
to give direct consent to being made the object of nontherapeutic experimenta-
tion, Ramsey holds that there is no ground on which any third party can legiti-
mately give consent on its behalf, vicariously or as a proxy either:
"I myself tend to believe that any use of the fetal subject, chil-
dren, the unconscious, the dying or the condemned would be an ,
abuse .... Seizing the 'golden opportunity' afforded by abor-
tion to exact — and falsely to 'presume' — acts of charity from the
fetus as a human research subject . . . can only mean a terrible
distortion of medical ethics to date, and of the Jewish-Christian
Tradition which was the foundation of its regard for the sanctity
of human life . "
Ramsey's position has the merit of cutting along a clean line. Like
Siegel, he would have fetal experimentation permitted only where it was directly
"related to promoting the life of the [particular] fetus." Richard McCormick,
by contrast, seems prepared to allow third parties (specifically, the parents)
a right to "vicarious" or "proxy" consent on behalf of the fetus, as on behalf
of a child, on certain strict conditions. How, then, does his argument rebut
Ramsey's unqualified case against nontherapeutic fetal research? It does so
(as I understand) by claiming that vicarious consent can be justified, provided
that it is directed at the question:
"What may it be presumed that the fetus ought reasonably to consent to,
if it were capable of understanding what is at issue, and taking this
decision for itself?"
since the fetus is a human creature, and so potentially a rational being, there
are certain things to which it ought to be prepared to consent, in virtue of
that potential rationality; and suitably qualified third parties (e.g., the
mother) are accordingly qualified to give its vicarious consent in these terms.
Father McCormick supports this conclusion by appeal to considerations from
"the natural-law tradition" to the effect:
"... that there are certain identifiable values that we ought to
support, attempt to realize, and never directly suppress because they
are definitive of our flourishing and well-being."
As he notes, this is not a position that depends on any specifically theological
dogma :
"Knowledge of these values and of the prescriptions and proscriptions
associated with them is, in principle, available to human reason.
That is, they require for their discovery no Divine revelation."
Nonetheless (I would comment) this is not a position that has won universal
agreement. Many people would argue in reply, for instance, that we do not have
a self-evident obligation to act rationally all the time, and that we cannot
reasonably impose such an obligation by proxy on a fetus. Carrying this line
of criticism further, Paul Ramsey himself replies that McCormick 's argument
actually imposes on the fetus an obligation to perform an implied act of charity
that, in an adult, would represent at best an act of supererogation; and this he
finds morally repugnant.
Speaking for myself, although I cannot wholly support Paul Ramsey's posi-
tion, I have great respect both for his • conclusion, and for the force of the
arguments by which he supports it. If members of the Commission hold that the
fetus is entitled to primary rights, and if they decide to recommend that the
present ban on nontherapeutic fetal research be continued, they can accordingly
do so with the confidence that such a recommendation can be given a firm ethical
foundation. ■ .■
The Case For a Restricted Program of Fetal Research ' ' •
There remains an intermediate position, which would permit a resumption
of nontherapeutic fetal research, on a restricted basis and subject to carefully
designed institutional controls. Among those who have prepared papers for the
Commission, both supporters and opponents of the view that the fetus can have
primary rights (e.g., Sissela Bok and Richard McCormick) have argued for variants
of this intermediate position; and, despite the force of Paul Ramsey's advocacy,
I would personally be inclined to join with this intermediate group.
For those who deny the fetus primary rights, the case for placing restric-
tions and controls on nontherapeutic fetal experimentation must rest, of course,
on the interests of other parties--on the direct interests of the parents in the
disposal of an aborted fetus, on the agony of mind to be expected in parents
10-7
from the fear of casual experimentation on their issue, and on the general risk
of brutalization in society, if medical research workers are permitted to handle
human beings and human tissues in a callous or arrogant manner. Sissela Bok ' s
paper accordingly gives prominence to the question at just what point in fetal
development these dangers become realistic, so that the use of the whole pre-
viable fetus for nontherapeutic research should cease to be permissible. For
those who would accord the fetus primary rights, on the other hand, it remains
necessary to reply further to Paul Ramsey's arguments. In my opinion, this can
be effectively done, if we make one small modification to the statement of
Father McCormick's case. Instead of following him in requiring that proxy con-
sent be directed towards the question:
"What may be presumed that the fetus ought reasonably to consent to,
if it were capable of understanding what is at issue, and taking this
decision for itself?"
We can alternatively pose the operative question in the form:
What may it be presumed that the fetus could not reasonably object to,
if it were capable . . . ?
This emendation does little to alter the practical substance of McCormick's
proposal, but it does avoid the objection of imputing "obligations" to the
fetus, in virtue of its "rational nature," and it does underline the force of
McCormick's requirement (in the case of nontherapeutic experimentation on chil-
dren) that such research should be attended by:
"No discernible risk, no notable pain, no notable inconvenience,
and . . . promise of considerable benefit."
For to declare that nontherapeutic fetal experimentation, in order to be morally
permissible, must be of a kind that the fetus itself, if cognizant, "could not
reasonably object to," suggests, on the one hand, that such experimentation
should be limited to (e.g.) the kinds of innocuous research investigations that
might be conducted incidentally on infants in a postnatal clinic, and would, at
the other extreme, certainly rule out any idea of (e.g.) stockpiling aborted
human fetuses in tissue or organ "banks." Accordingly, I conclude: Whatever
view the members of the Commission take about the fetus' entitlement to primary
rights, if they decide to recommend that the present ban on nontherapeutic fetal
experimentation be relaxed in favor of a restricted program of fetal research,
subject to careful controls and safeguards, they can again do so with the con-
fidence that such a recommendation can be given a firm ethical foundation.
Either way, however, the task of striking a balance between the risks of such
research, and the benefits to be foreseen from it, remains a highly delicate
one; and the key task of the Commission must be to devise appropriate safeguards
and controls.
For those who support a moderate position of this kind, therefore, the sub-
stantive problem immediately becomes one of striking such a balance between the
risks to which the fetus, the mother, and society would be exposed as a result
of nontherapeutic fetal experimentation, and the benefits that would presumably
accrue to medical science, and to humanity at large. As we shall see, this
intermediate program involves a substantial measure of agreement, about prac-
tical policies and controls, between both supporters and opponents of the
"primary rights" or "personhood" view. So, without at this point attacking the
underlying issues about "personhood," "viability" and the rest, I shall immedi-
ately turn to the question of risks and benefits, reserving the "personhood"
problem for later discussion.
III. IMPLICATIONS OF THE MODERATE CONSENSUS
Any policy for the licensing of nontherapeutic fetal experimentation on
a limited basis must be based (1) on an analysis of the actual risks and poten-
tial benefits involved, and (2) on the establishment of appropriate institutional
safeguards to monitor and control the application of that policy. The papers on
the ethics of fetal experimentation that are before the Commission provide signi-
ficant consensus about what we might call the "moral boundary conditions" within
which any such policy should be framed, in case a restricted program of non-
therapeutic fetal research is resumed. I shall draw attention to the key ele-
ments in that consensus here, while adding some additional comments of my own.
The Risks of Fetal Experimentation
In assessing the risks attendant on fetal experimentation, we should con-
sider separately three groups that are apparently at risk: the fetuses them-
selves, the mothers, and society at large.
As to the fetuses, from certain points of view, it might appear paradoxi-
cal that we should consider their interest at all. Father McCormick's paper on
"Proxy Consent in the Experimental Situation," for instance, links the exercise
of parental consent partly (though not entirely) to the child's prospect of
survival. Nothing should be done, by way of an experimental procedure, which
might reasonably be supposed to risk having deleterious effects on the child's
future welfare. To that extent (it would seem) the consequential arguments can
hardly be extended, as they stand, to a fetus which is due to be aborted. Yet
the papers submitted to the Commission are generally agreed that such a fetus
may nevertheless be exposed to two significant types of risk. First, there is
the risk of discomfort or pain during the experimental procedure, in the event
that its development is sufficiently advanced; and second, there is the risk of
deformed birth, in case the mother withdraws her consent to the abortion after
the experimental procedure has actually taken place.
Several papers mention the risk of pain and discomfort to the fetus in
passing, but none of them (in my view) pays close enough attention to the topic.
It seems somehow to be assumed that the questions of sentience is directly
linked to that of "viability," and discussion of fetal pain tends to switch,
almost immediately, to that of the fetus' capacity for autonomy or survival.
So let me underline here the fact that these two issues are, on the face of it,
quite independent. The question whether or not a fetus is capable of surviving
10-9
ex utero after being aborted has no obvious or direct bearing on the question
whether or not it is capable of experiencing pain and discomfort if subjected
to experimental procedures either in utero, before abortion, or ex utero, after
abortion, but before death. If it were clear that some fetuses are, in this
respect, "sentient" by (say) the sixth month of pregnancy, then there would be
an equally clear moral objection to employing painful nontherapeutic experi-
mental procedures on them at that stage, for in these circumstances the use of
such procedures would be quite straightforwardly cruel. At just what stage in
fetal development sentience may reasonably be supposed present, however, is a
question about which I have found regrettably little solid evidence. At what
stage, for instance, is the central nervous system sufficiently consolidated
for sentience to be a possibility? (Evidently much of the motor activity of
the fetus is purely reflex in character; but this is presumably less completely
the case the nearer the fetus approaches to full term.) I suggest that these
are questions about which the Commission should obtain testimony from impartial
experts. For there are certainly some kinds of fetal experimentation whose
permissibility would have to be made dependent, not on the "viability" of the
fetus, but on its sentience.
The other class of risks capable of affecting fetuses that are due to be
aborted springs from the possibility that the mother may change her mind about
the abortion after the experimental procedure is complete, and the fetuses may
subsequently be born deformed. As to these risks, two different proposals have
been made. Sissela Bok suggests an insurance scheme, to compensate mothers who
are left with the task of bringing up a deformed child, in consequence of such
a fetal experiment. Paul Ramsey refers (disapprovingly) to the view that experi-
ments should be undertaken only as a part of a single operative procedure,
designed to terminate with the abortion. This would normally obviate the possi-
bility of the mother's revoking her consent after the experiments have taken
place. Both suggestions (in my view) deserve serious consideration by the
Commission, though I am personally inclined to think the latter proposal is
the more satisfactory one. In a case of this kind, after all, the financial
burden is the least of the agonies a mother will be exposed to, and it would be
preferable to design our operative procedures in a way that spared her the
other, more painful, psychological and personal burdens. At the same time,
Sissela Bok ' s proposal does have the merit of drawing attention to the important
question (also referred to by Joseph Fletcher) of who is to take responsibility
for the future welfare of those fetuses, or premature infants, whose lives are
preserved by medical intervention after a late abortion against the wishes of
the mother, especially when they are too frail or deformed to be suitable sub-
jects for adoption. (In a suitable social political environment, a case might
be made for regarding such children as "wards of the State," and for assigning
them to publicly-financed foster homes, rather than obliging their mother to
raise them, even with the help of insurance benefits.)
The risks of nontherapeutic fetal experimentation to the mother are not
in dispute, and it is generally agreed by the members of the present panel that
the proposal to perform such experiments should never be made the reason for
delaying a planned abortion. On the one hand, the experimental procedures them-
selves may be a direct source of pain and discomfort; on the other hand, they
may have longer-term medical consequences; and, either way, any delay in the
10-10
abortion is generally undesirable. There is much to be said, therefore, in
favor of Paul Ramsey's argument that — if there are to be fetal experiments at
all — they should, at most, be combined with the actual abortion procedures.
In addition to the possible physiological effects of fetal research on
the mother, however, these risks have another side also, to which the papers
before the Commission give (in my view) too little attention. The psychological
aspects of pregnancy and abortion are a subject about which too little is known;
but we do at least know enough to recognize that it would be morally wrong to
disregard a woman's psychological investment in a pregnancy, and in the issue
of that pregnancy. Whatever the circumstances in which a pregnancy is termin-
ated, the mother should have confidence that the issue will be handled and
disposed of, both before and after death, in a respectful and humane way; and
the lack of such an assurance would be a legitimate source of grief and guilt.
This represents, therefore, an additional element to be taken into account in
judging the potential damage to be guarded against in fetal research. (I shall
return to this topic at the end of this paper.)
More attention is paid in the papers to the risks affecting society at
large, in case nontherapeutic fetal research is permitted, either at all, or
without being subject to adequate controls. In this respect, the fear is one
of "brutalization, " i.e., a fear that any relaxation in the general feelings
of reverence and concern towards the tissues and remains of the dead and dying
could give the color of extenuation to other forms of callousness, violence
and human indifference. It may be questioned whether, as applied to fetal
research in particular, these fears are in fact realistic; every apprentice
physician is exposed to the disecting room as a part of his normal training
and, by the time he is medically qualified, his attitudes to human tissues and
cadavers will have been effectively formed and tested. So, it is not clear
that a properly-regulated program of fetal research can, in this respect, have
any novel effect on the attitudes of physicians and medical researchers.
On the other hand, the existance and currency of these fears is itself
a matter of importance and moral relevance, as well as being a significant
element in the social context of the Commission's proceedings. The sources of
this fear are not hard to trace. Over the last 25 years, the public's image of
the physician has changed. Traditionally, the general practitioner of medicine
was one of those people — along with the local priest or minister, and perhaps
the family lawyer--to whom the individual could turn for advice, in absolute
confidence that any advice he received was concerned wholly with his personal
welfare. The family doctor had no perceptible conflict of interests: his whole
position was dependent on his capacity to act as a fully-committed personal
advisor. Even after a patient was admitted to the hospital, he could still look
to his family doctor to represent his interests unhesitatingly, and to rescue
him, if need arose, from the hospital's bureaucratic toils. The new alliance
betv/een attendant physicians and medical research scientists has brought that
implicit confidence into question. Many people today, as a result, actively
feel for the first time something less than certain whether the medical advice
they get is purely directed at their own individual benefit, or whether it is
in part motivated by other concerns, e.g., by the research interests either of
the attendant physician himself or of his colleagues. (This uncertainty has
10-11
been only aggravated by the growing shift in the locus of medical practice, from
the bedside or private consulting room, to the hospital clinic.) So the current
public image of the physician is in course of being transformed from the friendly
and totally trustworthy one of the "family G.P.," to the intimidating and psycho-
logically opaque one of the "white-coated" scientist.
No doubt this transformation in public attitudes has gone too far, and I
am not in any way claiming that it is justified. Still, this change itself has
made it possible for public feelings about abortions and fetal experimentation
to be inflamed beyond a realistic level, to the point at which the collaboration
between attendant physicians and biomedical scientists can sometimes be made to
appear an "unholy alliance" for promoting scientific knowledge, in disregard of
patients' interests. Given the resulting disquiet, the actual fear of brutali-
zation becomes as relevant a feature of the ethical situation as the objective
risks of brutalization; and any procedures for supervising human experimentation
in general, and particularly fetal experimentation, must take it into account.
For this reason among others, the general public has a legitimate moral interest
in being adequately represented on the ethical and human experimentation commit-
tees of all hospitals in which nontherapeutic fetal experimentation is to be
undertaken. Such lay representation will, of course, not just protect the public
against the possibility of overenthusiasm or malpractice on the part of research
workers, but also protect the research scientists themselves against uninformed
or ill-motivated outside criticism.
There is one other source of public disquiet, which takes us beyond the
scope of the Commission's immediate recommendations, though not beyond its topics
of discussion: let me simply mention this in passing. Some years ago, it was
demonstrated at Cambridge University that a newly fertilized human zygote could
be kept alive in vitro for a period of days, during multiple cell-divisions, and
this demonstration drew widespread public attention. The resulting outcry about
"test-tube" babies played on fears and hostilities towards science that have
roots in the Middle Ages, if not in antiquity. This episode is relevant to the
present controversy about fetal research. If we carry the discussion of
"viability" to its final conclusion, the question indeed arises whether it will
not eventually be possible to engage in "zygote culturing," and even to bring
an embryo to full term outside the mother's womb. If this were ever practicable,
there might well be situations in which it was both medically desirable and
ethically permissible to bring a child into life by in vitro gestation. But
another application of the same techniques would make it possible also to mass-
produce human tissues and embryos for use in scientific experimentation, and it
is my sense of the matter that people of most persuasions find the prospect of
such "zygote farming" morally repugnant. Whatever their position on the "person-
hood" issues, they would see such a practice as inevitably encouraging unaccept-
ably casual and arrogant attitudes towards the control of human life.
The Benefits of Fetal Experimentation
Surely, none of those who have prepared papers for the Commission on the
ethics of fetal research has any doubt about the positive value of improving
medical knowledge. The implication apparent in some speeches at the National
10-12
Academy of Sciences discussion, that those who raised moral objections to unsuper-
vised, nontherapeutic fetal experimentation are "against science," is accordingly
beside the point. The question is not whether our medical knowledge about preg-
nancy and fetal development ought to be improved by all legitimate means at our
disposal, but rather how far this is to be done without lapsing into morally
unacceptable procedures. So it should go without saying, here, both that fetal
experimentation holds out the promise of genuine and substantial benefits to
"medical science"--both directly, to pediatrics and obstetrics, but also to
general physiology, pathology and medical therapeutics--and that those benefits
can reasonably be expected to carry over to "humanity" in general, as the new
techniques of biomedical science become incorporated into actual medical prac-
tice. If ethical questions must, nevertheless, be raised about these benefits,
those questions have to do with the sad yet realistic need to satisfy ourselves
that these beneficial results are being achieved in fact, and not sidetracked
into directions to which legitimate objection might be taken. So it is desirable
to introduce, at this point, a word of caution about the intended beneficiaries
of fetal research: viz., "medical science" in the first place, and "humanity" in
the second.
As to medical science: the same public disquiet that shows itself in fears
that fetal experimentation might encourage "brutalization" extends also to hesi-
tations about the personal motives underlying the medical scientist's own research.
The suspicion is that, in some cases, the legitimate theoretical goals of medical
science may eventually become partly confused in the minds of those human agents
who are personally engaged in fetal experimentation, with the satisfaction of
their intellectual curiosity or the personal achievement; so that a proprietary
attitude towards their own research may lead them to expose fetuses or fetal
organs to experimental manipulation praeter necessitatem. (This anxiety, too,
was reportedly evident in the National Academy of Sciences discussion.) Once
again, these hesitations may well be groundless in all but a tiny minority of
cases. But, in so delicate a field as that of fetal research — as in all matters
involving the possibility of delicate conflicts of interests — it is not enough
that justice should in fact be done: it must also be seen to be done, in a
visible and verifiable manner. Once again, therefore, I am led to conclude that
the general public has a- legitimate moral interest in being represented by lay
assessors on hospital ethical and human experimentation committees. Such lay
assessors could satisfy themselves, on the public's behalf, that nontherapeutic
fetal experiments were being approved only in cases where it had been demon-
strated that their results held genuine promise of contributing substantially
to the legitimate therapeutic goals of science, and that no alternative ways
were available of arriving at the same discoveries. Once again, also, the fact
that experimental protocols had been scrutinized by lay assessors would protect
biomedical scientists from uninformed outside criticism, as effectively as it
would reassure the public about the actual conduct of fetal experiments.
The claim that better medical science is a good for humanity in general
also needs qualifying in one significant respect. We may, of course, discount
loose and uncritical claims of this kind when they are made by the public
spokesman for medical research in their advocacy of increased funding for bio-
medical science; but it must be noticed that even Richard Mccormick's account
of "what any rational being ought to want, and so ought to be ready to promote,"
takes it for granted that the improvement of medical science is of benefit to
all of humanity. In an ideal world, this might well be the case. But we should
take a moment to inquire who will in fact be the primary beneficiaries of the
therapeutic advances made possible by fetal research.
Many of the panel members, notably LeRoy Walters and Paul Ramsey, have
pointed out the limitations to the claim that categorical suffering on the part
of the child or a fetus now is justified by hypothetical benefits to children
or fetuses in later generations. It is one thing for a father (say) to make a
sacrifice now, of which his own children can expect to be the beneficiaries
after his death; but it is quite another matter for an individual to suffer
pain now, in order to do hypothetical good to some unidentifiable class of
possible beneficiaries at some indeterminate future time. What is morally
questionable about such appeals to charity is not just the hypothetical char-
acter of the resultant goods: we must also satisfy ourselves that there is no
evident systematic differentiation between the class of those who are to suffer
now and the class of those who are to benefit later.
E.H. Carr, the historian, has wisely commented on the political demand that
the Russian people of the 1920s should "sacrifice their present comfort for the
benefit of future generations," pointing out that all such demands are in prac-
tice intrinsically inequitable: the class that pays is always quite other than
the class that benefits. If we are to justify nontherapeutic fetal research in
similar terms, we must therefore be sure that we are not building any comparable
inequity into our practice. At once, certain reservations suggest themselves.
Suppose, for the sake of argument, that the class of pregnant women predomi-
nantly involved in fetal experimentation were taken from the poorest members of
the population, while the class of those who predominantly benefitted from the
resulting therapeutic advances were taken from the richest. The effect of this
would be to introduce a substantial and morally relevant inequity into the
actual practice of fetal research.
This supposition, whose racial implications do not need to be made expli-
cit, is not an entirely idle one. There is an evident suspicion — as discussed
again below, in connection with the problem of consent — that "free" hospital
abortions, especially second-trimester abortions, may in some cases be "traded"
to indigent parents, in return for consent to participate in fetal experimen-
tation. As before, the significant issue here is not whether this suspicion
is well-founded, but the fact that it arises at all. For the reasons already
indicated, therefore, I would myself hope that the proposed National Commission
for the Protection of Human Subjects will accept responsibility for monitoring
the social incidence of human experimentation in general, and particularly of
fetal experimentation. A well-documented assurance that the burden of human
experimentation was not being borne unduly by any one section of the population
would both provide the public with legitimate peace of mind, and shield fetal
research workers from any charge that their research was conducted in an inequi-
table or discriminatory manner.
10-14
Balancing Risks Against Benefits
Father McCormick has indicated that, in his view, the possibility of
justifying nontherapeutic fetal experimentation depends on an appropriate
balance of risks against benefits. He offers us two complementary criteria:
(1) the risks involved must be low, and the prospective benefits high enough
to outweigh them, and (2) there must be no alternative route to the same results.
It states in quite general terms, these propositions might win support from a
majority of panel members. (Even Paul Ramsey suggests at one point that his
opposition to McCormick 's position might weaken, if the criterion of "low risk"
were applied stringently enough.) Furthermore, these criteria have the merit of
covering quite generally all types of experimental procedure applicable to the
complete fetus itself, whether in utero or ex utero before death. But there are
some significant differences between the panelists when it comes to spelling out
the rules governing their actual application in practical situations.
Thus, Sissela Bok recommends that the United States follow the British
guidelines in laying down a specific term and/or weight as the index of "fetal
viability," and in ruling that "the use of the whole previable fetus [in non-
therapeutic experimentation] is permissible, provided that only fetuses weighing
less than 300 grams are used." This recommendation appears to me too undiscrim-
inating to meet McCormick 's requirements. Let me set aside for the moment the
question, whether "viability" — which Bok admits to be a "fluid and shifting con-
cept"— is the relevant issue at this point. Quite aside from that, I would
question whether it is 'morally appropriate to draw only a hard-and-fast line,
dividing one class of fetuses which may not be used in nontherapeutic experi-
ments at all from another class of fetuses which may (it seems) be used in any
scientifically justifiable experiment. Surely, the question whether the use
of a fetus in nontherapeutic experiments is permissible at all, is not the only
question: we must ask also what kinds of experiments are permissible for a
fetus with given characteristics. So, while there may be reasons for laying
down some definite upper size-limit, above which aborted fetuses may not be
made the subject of any experimentation, it will probably be necessary also to
balance off "risks" and "benefits" further, by establishing guidelines governing
what types of procedures may or may not be undertaken on fetuses at different
stages of development below that upper limit. In the event that a restricted
program on nontherapeutic fetal research is resumed, indeed, one may foresee
that the actual practice of human experimentation committees in research hospi-
tals will come to be based, not on any single, hard-and-fast "index of permissi-
bility," but rather on a more discriminating body of "case law" and "precedents";
and it should be one responsibility of the National Commission for the Protection
of Human Subjects to keep a watchful eye on the development of that "case law."
The problems that arise over the use of "the whole previable fetus" are
less severe, however, than those that arise over the use of organs, tissues,
etc., from aborted fetuses, in place of (say) animal organs, tissues, etc., in
cancer research and similar fields of inquiry. Over this question we face
serious practical difficulties, as well as difficulties of medical ethics, in
determining a "cut-off" point beyond which such use is impermissible and in
setting appropriate criteria of "fetal death." If the experimental use of
fetuses below 300 grams in weight is approved, it is presumably also supposed
10-15
that a fetus must be clearly dead before organs or tissues may be removed for
study. Yet what tests of "fetal death" are envisaged? As Bok points out, the
proposed DHEW guidelines 46.307 (d) and (e) are substantially more restrictive
in this respect than the British Peel Commission recommendations; in partic-
ular, paragraph (e) which lays down that "experimental procedures which would
terminate the heartbeat or respiration of the abortus will not be employed."
Bok herself would remove this latter restriction, and would permit researchers
to perform experiments which might accelerate the death of the fetus. On this
issue I personally favor 46.307 (e) , and consider the further problems raised
by suspending it too serious to set aside. It could be argued, no doubt, that
a "previable" (and so presumably nonsentient) 250-gram abortus, which has no
hope of surviving more than a short time anyway, has "nothing to lose" by
meeting an accelerated death at the hands of an experimenter, so that dismem-
berment should not be regarded as involving an "injury" to such a fetus. But,
while I share Bok ' s sense that the risk of causing pain to the fetus is the
most weighty consideration, I still find it hard to go along with her acceptance
of the Peel Commission's less restrictive recommendations. Even in the case of
a 250-gram fetus, I myself still feel the force of the analogy with McCormick's
argument that we cannot properly consent by proxy to a child's (e.g.) giving up
a kidney for a transplant operation.
Rather, the questions at issue here appear to me strictly parallel to
those which arise in obtaining suitable hearts, or other complete organs, for
transplantation operations. On the one hand, the success of such operations
depends on the availability of organs that are still (so to say) "fresh"; on
the other hand, in the case of heart transplants particularly, this has on
occasion meant removing the organ from a (euphemistically called) "donor" at a
time when his actual death was still problematic. The question at just what
point it should be permissible to remove organs from a dying patient, for trans-
plantation to another patient, has been much argued over the last 10 years.
(I would particularly refer to the 1968 Beecher report in which the loss of
brain function in an irreversible coma is suggested as marking a significant
point of transition on the passage from life to death.) Like Ramsey, Walters
and Siegel, I believe that "the criteria for ascertaining death in the fetus
should be consistent with the criteria applied to other organisms," and more
specifically with the criteria relevant to human organ transplantation operations.
The difficulty of deciding under what circumstances the removal of fetal
organs or tissues for study would be permissible is particularly acute, for a
reason that may at first sight appear merely technical. The abortion procedures
commonly used in the early months of pregnancy — at a stage when the fetus is
clearly presentient and "previable" — are of kinds that gravely damage or destroy
the fetus and its organs. It is only in cases of hysterotomy, or comparable
procedures, that an entire live fetus is recovered from an abortion; and, by the
stage in pregnancy at which these more drastic procedures are justifiable, we
are approaching the point at which legitimate questions can be raised about
"viability" and sentience. Evidently, if it were a simple matter to obtain
experimental material from the detritus of a simple six-week miscarriage or an
early D and C — in which case it would probably be inappropriate for the mother
to claim any serious "psychological investment" in her issue — the difficulty
would not arise with the same force. As matters stand, however, the point in
fetal development at which we have unambiguously crossed the line dividing the
detritus of a D and C, on the one hand, from a sentient being on the other, is
inconveniently close to that at which destructive procedures of abortion have
to give way to nondestructive procedures, such as hysterotomy. (I shall argue
later that this may not be a mere coincidence, but that it is relevant to the
task of clearing up the ambiguities surrounding the concepts of "viability"
and "personhood. ") At any rate, it is only in the case of hysterotomies and
the like that the question of experimental dismemberment becomes an active one,
and the fetuses available for this purpose seem, all of them, to be within
significant range of sentience and "viability."
The Problem of Consent
The other practical topic discussed at length by the panel is that of
consent, and consent procedures. What parties can claim authentic legal or
moral interests in the issue of an abortion, whether spontaneous or induced?
And what sorts of consent procedures should be required, in order to respect
those interests and give the various parties proper opportunities to exercise
any corresponding "rights" in the disposal and handling of that issue? I will
summarize the outcome of these discussions under three heads: Fetal Consent,
Maternal Consent, and The Interests of Third Parties.
Fetal Consent
Evidently, the question of fetal consent is a purely theoretical one; but
it is one over which (as we have already seen) a good deal turns, particularly,
in respect to the mother's own standing in the matter. Granted that there is no
question of obtaining consent to nontherapeutic experimentation from a fetus
directly, as one can from an informed adult, two questions arise. Is it (1)
necessary and (2) possible to obtain a satisfactory equivalent in the form of
vicarious or proxy consent? Three main answers are represented in the papers
before the Commission. In the first place, we can declare fetal consent to
nontherapeutic experimentation both indispensible and unobtainable (as Paul
Ramsey does); and so condemn all such experimentation as unethical. In the
second place, we can declare fetal consent unnecessary, on the grounds that
the fetus itself has no legal or moral standing and therefore no formal
"interests" in the case (as Sissela Bok does) ; and we can then give the mother
primary rights of consent directly, rather than vicarious or proxy rights, that
are now unnecessary. Or, in the third place, we can accept fetal consent as
necessary, but infer or presume it (as Richard McCormick does) on the basis of
proxy decisions taken vicariously by the parents, regarded as having the
interests of the fetus at heart. Given the borderline nature of the present
case, all three positions seem to me to run into some difficulties on a theo-
retical level. For practical purposes, however, the differences between them
become significant only when we turn to consider what other parties have authen-
tic claims and how they should be exercised.
Maternal Consent
As to the mother's rights of consent or veto, we have one clear starting
point. In the case of a full-term infant, there can be no doubt of the mother's
right to approve or veto the use on her infant of any experimental procedure,
particularly a nontherapeutic one. We may therefore take as our starting point
the question under what circumstances, if any, a mother could forfeit that right
to have a say in the treatment or disposal of her issue.
In the Senate sub-committee testimony and elsewhere, there has been elo-
quent advocacy of the view that a mother forfeits this right simply by choosing
to have an abortion, so that she should not have any right of veto over the use
of the resulting fetus for experimental purposes. By electing an abortion (it
is argued) the woman "puts her own welfare before that of the fetus," and so
destroys the presumption on which proxy consent depends: viz., that she "has the
interests of the fetus at heart."
wo
This view finds no serious support from the panel, but its weaknesses are
irth spelling out here since they embody some influential confusions. Four
different counter arguments can be offered against it, all of which tend to
strengthen the presumption in favor of a maternal veto on nontherapeutic fetal
experiments .
1. The argument for forfeiture rests on a false assumption. Very rarely
can the decision to terminate a pregnancy be represented as being merely the
mother's choice "to put her own welfare before that of the fetus." It is com-
monly an agonizing decision, in the course of which many considerations are
weighed, including the fetus' own interests. (The argument, "it would not be
right for me to bring this child into the world in my present circumstances,"
is not necessarily a self-deceiving one.) Whatever one may think about the
mother's motives in one or another particular case, accordingly, the argument
offered gives no grounds for an automatic forfeiture of rights by the very
decision in favor of abortion.
2. All question of motives apart, the mother retains the normal psycholo-
gical stake in her issue, which demands respect whether the pregnancy is ter-
minated naturally or by surgical intervention. This psychological investment
is, of course, not a mere matter of conventional sentiment. It is associated
with physiological, particularly hormonal, changes which are disrupted at abor-
tion with consequences that should not be lightly disregarded or dismissed as
morally irrelevant. (LeRoy Walters cites an interesting side argument at this
point: viz., that the right of parental consent for medical or surgical proce-
dures on children is derived from the parents' continuing personal and financial
stake in the child's future— the parents will have to go on taking responsibility
for the child after the treatment, whatever its outcome, so they should have the
chance of vetoing it— in which case the right of consent would again lapse on
abortion which spares the parents any need to take subsequent responsibility for
the fetus. But here too we can reply that the parents' psychological stake in
the child goes far beyond that created by future caretaking responsibilities,
so forfeiture again does not follow. )
10-lf
3. The analogy advanced by supporters of the forfeiture argument, viz.,
that a mother who chooses an abortion is like a parent who abandons a child,
does not serve the required legal purpose. Although abandonment of the child
no doubt calls in question a parent's fitness to retain custody of that child,
few jurisdictions would treat it as entailing automatic, still less irrever-
sible forfeiture of all parental rights. By abandoning a child one loses at
most only some parental rights. Law and custom alike require us to take care
to respect the wishes of parents or other next-of-kin, especially in respect
of the disposal of the dead, whatever may have been the state of personal
relations between the deceased and his survivors.
4. Most significantly in the context of the present discussion--even if
a mother could forfeit or renounce her rights and responsibilities towards her
offspring in any way, those rights and responsibilities would in no case fall
automatically to the nearest medical research scientist, or even to the atten-
dant physician. Rather, the offspring would merely become a ward of the State,
which would have the responsibility of acting in loco parentis . So, the onus
of obtaining consent to nontherapeutic experimentation would not be removed:
its locus would merely shift from the mother to the competent authority of the
State.
Accordingly, there appears to be no basis for the suggestion that hospi-
tals should be free to assume full rights and responsibilities over the issue
of abortions, in disregard of the mother's wishes. This conclusion is not
affected by the Peel Commission's argument that it would cause "unnecessary
suffering" to obtain consent for experimentation from the mother, under the
circumstances of an abortion. (That is a comparatively straightforward matter
of consent procedures, and I shall return to the question below.) While mater-
nal consent may not by itself be sufficient to authorize the use of a fetus for
experimental purposes, therefore, it should normally be a necessary requirement;
while a maternal veto should in all cases by treated as final.
The Interests of Third Parties
Can any other parties, besides the mother, plausibly claim any interest
in the disposal of an aborted fetus? In different ways, claims of five other
parties need to be considered.
1. Where the abortion takes place within a marriage, the father can claim
certain moral and even legal rights in respect of all his offspring — including
aborted ones — and some of these moral rights, at least, might well be extended
also to the presumed father, even where conception has taken place out of wed-
lock. (In both cases, too, some degree of psychological investment can reason-
ably be argued.) On the other hand, in many out-of-wedlock pregnancies the
father may be unidentifiable, unavailable or indifferent, so that his interest
in the offspring may reasonably be regarded as having lapsed. As a general
guideline to the subject of paternal consent, therefore, one could suggest the
twofold rule: (a) where a father is either present or in effective touch with
10-19
the mother, he should also have the right of veto over nontherapeutic experi-
mentation on his offspring, and (b) where the father is neither present nor
in effective touch with the mother, no special effort need be made to obtain
his consent.
2. We may consider the attendant physician at the delivery and also the
research scientist who proposes to perform an experiment on the fetus. In both
respects, the relevant moral issues seem to be well taken care of by the Peel
Commission's recommendation, 4(iii):
"The responsibility for deciding that the fetus is in a category which
may be used for this type of research rests with the medical atten-
dants at its birth and never with the intending research worker."
In particular, the medical research scientist should not normally play any
direct part in the decision either to abort or to approve the issue of an
abortion as suitable for any particular class of research.
3. A specific public interest is involved, notably, in insuring that the
"separation of powers" between the attendant physicians and the research scien-
tist is respected and observed. Here again, we must not ignore the element of
distrust or disquiet that has grown up recently — the suspicion that hospital
physicians and research scientists are to some extent "in collusion" — even if
we consider it without foundation. The more groundless this distrust may be,
indeed, the easier it will be to accept a simple procedural provision that can
set it at rest. For this purpose I would recommend that the proposed lay asses-
sors on the human experimentation committees of research hospitals (referred to
earlier) should have the further responsibility of satisfying themselves that
decisions about abortion, and about making an aborted fetus available for
experimentation, are in fact being taken in accordance with these general rules.
4. In addition to this general public interest, there is a specific State
(or Federal) government interest in the disposal of aborted fetuses. The issues
that arise in this connection involve somewhat technical problems of law, rather
than ethical problems. But, evidently, the existing responsibilities of the
Registrar of Births and Deaths, and of the Coroner, whether in respect of births,
deaths, and/or stillbirths, together with the rules about the timing and legal
implications of registration, must extend in certain respects, and on certain
conditions, to aborted fetuses. In a situation where ambiguities in the law
have already led to criminal prosecutions, indeed, the legal rules in question
are in urgent need of clarification. This is particularly urgent if, as Sissela
Bok proposes, the Commission follows the Peel recommendations, in permitting
fetal experiments in which the death of a "previable" fetus is accelerated by
the experimental procedure itself. Over this delicate point, a clearer set of
rules and sympathetic cooperation between a research hospital and the local
coroner's office could do as much to protect the legal standing of fetal experi-
menters as it does to insure that the State (or Federal) government's rules are
being respected.
10-20
Consent Procedures
In general, the point at which the Peel Commission recommended code of
practice appears, at this distance, to be vaguest and least satisfactory is
over the procedures for obtaining and documenting parental consent to fetal
experimentation. Three points need to be made:
1. I referred earlier to the Peel Commission argument that, in cases
where "the separation of the fetus from the mother leads to the termination of
its life," to seek parental consent for the use of a fetus in experimentation
"could be an unnecessary source of distress to parents." This argument would
carry weight (in my view) only if the consent were deferred until after the
abortion. There is no evident reason, on the other hand, why consent for the
experimental use of tissues or organs from the fetus should not be given or
denied before the abortion, at the same time, and on the same document, as
consent to the operation itself. (The Peel Commission in fact goes on to make
a very similar proposal.) Apparently, the consent or denial would have a
different legal standing in different situations: e.g., it might have binding
legal force only in case the fetus were delivered alive. But one might hope
that hospitals would not be too ready to disregard parental wishes, even where
these were not legally binding.
2. There is an evident risk involved, nonetheless, in the use of such a
combined form. The Peel Commission's requirement 3(iv), viz., that there is not
monetary exchange for fetuses or fetal material must be understood as covering
not merely open monetary exchanges, but also "barter deals"; and there is a
need to guard against the possibility that indigent parents might come to regard
consent to the experimental use of tissues as an implicit "price" for obtaining
a free hospital abortion. It is both ethically and socially important that any
such "payment in kind" be clearly brought under the scope of any recommendation
against "monetary payment" for the use of fetuses or fetal material.
3. Something much more specific needs to be laid down about the form of
consent proposed and about the manner and circumstances in which maternal or
parental consent is to be obtained. Consent or denial of consent must be
directly documented on a form which, if need arose, would be available to a
competent Court for review. Furthermore, it should wherever possible be given
not just in the presence of the attendant; physician alone, but to the satis-
faction of a third party representing the public interest. (A hospital social
worker, acting on behalf of the lay representative or representatives on the
human experimentation committee of the hospital, would be a suitable person.)
One needs only a limited exposure to the problem of consent to understand that
"informed consent" is an ideal rather than an easily attained result. In so
delicate a situation as that of a mother consenting to the use of her aborted
fetus for experimentation, however, it is certainly desirable that every rea-
sonable step be taken to insure that her consent is as clearly and fully
informed as is practicable: not least, because care taken at this stage may
serve to alleviate, later on, the psychological shock and grief which are prob-
ably an inevitable consequence of the abortion and everything associated with
it.
10-21
IV. APPENDIX
Two general subjects of a more theoretical kind need to be commented on
in conclusion. These are (1) the dispute about "personhood, " "viability" and
related concepts; and (2) the psychological aspects of pregnancy and abortion
and their moral relevance to the rights of the mother over her issue.
Personhood, Viability and Quickening
The public debate about abortion and fetal research has given great prom-
inence to the question, "Is the fetus a person?"; while the papers before the
Commission concentrate rather on the question, "In what circumstances is a fetus
viable?" Both questions are evidently intended, in part, to give more preci-
sion to a widespread sense that the changes taking place in the course of preg-
nancy, both in the development of the fetus itself and in the mother/fetus
relationship, justifies us in taking a very different attitude — both legally
and morally — towards abortion and experimentation at different stages in the
process. (In respect to the first couple of months, there may be much force
in the argument that a newly implanted embryo or early fetus is analogous to,
say, tonsils, or a benign tumor; whereas, in respect of the final trimester of
pregnancy, this would certainly not be an acceptable analogy; yet, by what
criteria are we to draw the line between these two phases in pregnancy?) Neither
of these two ways of posing the question is, however, capable in my view of
clearing up the existing difficulties. What is needed, if this issue is to be
clarified, is a more careful analytical scrutiny of the distinctions and inter-
relations between no less than six different concepts, which are frequently run
together at present under one or another of the two words, "personhood" or
viability"; and such an account can be given in a fully acceptable form only
a posteriori , i.e., in the light of detailed expert testimony about the actual
changes involved in the successive months of pregnancy.
This is not the place to provide the fully detailed analysis required for
this purpose. But it will be worth drawing some first distinctions here, and
indicating how easily cross-purposes and confusions can arise if these distinc-
tions are not clearly respected. At one extreme, then, we can recognize (1) the
strictly legal use of the term, "person." To be a "person," in this sense, is
to have a standing before the Courts, and so to be able to bring an action,
either directly and in person, or through a legally qualified representative.
In this sense, of course, a corporation can be a "person," and so is a newborn
child — on whose behalf a parent can sue ex parte, as legal guardian — but it has
now been definitely ruled that a fetus is not a "person" in this sense. For
judicial purposes, that is to say, "personhood" begins only with a live birth,
though nothing need follow from that fact about "personhood" as defined in other
senses or for other purposes. In particular, the judicial withholding of legal
rights from the fetus does not by itself settle the question under what con-
ditions a fetus is entitled to primary moral rights. Rather than rest the dis-
cussion throughout on the ambiguities of the term "person," therefore, I have
set out the issues raised in this paper explicitly in terms of the question,
whether a fetus has moral rights and interests of its own, as contrasted with
those of its mother.
At the other extreme, there is (2) the very broad term, "living." Nobody
in this debate would presumably trouble to deny that a newly implanted zygote,
or early embryo, is "living" or "alive," at least in the sense of being composed
of living cellular tissue; and this fact alone differentiates it from (say) nail-
parings. Even so, there is a distinction to be drawn between recognizing an
early fetus as "living" and acknowledging it to be a creature "capable of inde-
pendent life"; for instance, not every piece of actively developing living
tissue (e.g., a carcinoma) is independently "viable" in any sense of that term.
Somewhere between the two extremes there is (3) the Aristotelian notion of the
embryo as "potentially human," or "potentially rational." It may well be helpful
to apply this notion, as Richard McCormick does, as a basis of discussing the
moral status of the fetus, in terms of the natural-law tradition; but it appears
to me an insecure basis for attributing primary rights (or "personhood, " in an
extra-judicial sense of that term) to the embryo or zygote from the moment of the
implantation, or even fusion.
For the purposes of the Commission's deliberations three further concepts
are more directly relevant, but also more problematic. On the one hand (4) the
term "viable" is defined (though not, by implication, used by the members of the
present panel) in a sense that is strictly relative to the life-support tech-
niques and equipment available at a given time and place. A fetus will, in this
sense, be "viable," if and only if it is capable of being brought to the point
of independent life, with the help of techniques and equipment available where
and when it is delivered. Viability, in this sense, might be a legitimate term
to apply in discussing ^he responsibilities of the medical attendants engaged
in an abortion, but it is a most unsatisfactory criterion for laying down any
kind of moral or ethical doctrines about the intrinsic state of the fetus
itself, at one stage or another in pregnancy. For are we to put ourselves in a
position where our ethical attitudes towards a fetus, and its possible moral
status, are entirely dependent on the state of medical technology? (To go to
the extreme: if methods of "zygote culturing" were brought to the point at
which in vitro gestation became a real possibility, we might then be forced
to say that every fresh zygote had, in principle, been thereby rendered "viable";
And we surely would not wish to say, on that account alone, that there was no
longer any such class of things as "previable fetuses"?)
My own sense of the matter is that the term "viable" is, at this point,
standing in for one or another of two further concepts, neither of which is
made fully explicit in the papers before the Commission. One of these can be
referred to by (5) the term "sentient," which I have used more than once in
this survey. Sissela Bok ' s references to the risk of causing pain to the fetus
clearly presuppose some such idea of "fetal sentience," though she does not dis-
cuss explicitly the question of how close the capacity to feel pain is connected,
in her view, with "viability." On that subject, as I suggested in the body of
this paper, expert testimony is needed; and I am not myself convinced that suffi-
cient knowledge of the development and consolidation of the fetal brain and
central nervous system, during the second trimester of pregnancy, is yet avail-
able to settle the matter adequately.
On the other hand, there is no doubt that certain very striking changes do
occur in the fetus, in reasonably close proximity, during that second trimester.
In addition to — and in consequence of — the consolidation of the nervous system,
the fetus becomes autonomously active, so that the mother herself begins to
regard it less as a part of herself than as an independent creature, if not an
actual "opponent"; while, at the same time, it begins to move towards that domi-
nant position in the pregnancy, as a result of which it eventually appears to be
capable even of initiating the onset of labor. Much of this is hinted at in (5)
the use of the traditional terms, "quick" and "quickening." The history of these
terms is examined in the Supreme Court's judgment in Roe v. Wade, 410US113 (1973).
Quickening was commonly associated with the period around the sixteenth through
the eighteenth weeks of pregnancy; and, before the New York statute of 1828, the
abortion of a prequickened fetus was not regarded as a criminal offense. As
Chief Justice Blackmun pointed out in the majority opinion (pp. 132-133) :
"The absence of a common-law crime for pre-quickening abortion appears
to have developed from a confluence of earlier philosophical, theolo-
gical and civil and common-law concepts of when life begins."
It is around the same period that the fetus also acquires that recognizably
"human" form which was canonically required for baptism of a premature child
or fetus .
It is not my intention to revive the issues covered in Roe v. Wade. My
point is simply to suggest that the Peel Commission and others have tended to
use the modern-looking but intrinsically confused term, "viable," not in the
sense discussed above under (4) , but rather as an approximate synonym for (6) ,
i.e., the traditional term, "quick." No doubt, some real precision could be
added to our understanding of that term if we were to bring all our new medical
and scientific knowledge about pregnancy and fetal development to bear on its
definition; and, once again, this raises issues about which expert testimony is
required. But, as so often, a great deal of morally and legally relevant human
experience was built into the common law over the centuries of its evolution;
and this experience is directly relevant to our own problems here. As I myself
read many of the contributions to the present discussion — e.g. , the Peel Commis-
sion's recommendation that "the use of the whole previable fetus is permis-
sible . . . ", and Sissela Bok's commentary on this recommendation — it would
clarify their sense if we were to drop entirely the terms "viable" and "pre-
viable," with their misleading allusions to the current state of medical tech-
nology, and substitute either the traditional terms, "quick" and "prequickened,"
or some up-to-date refinement of them which would refer directly to the new
kinds of fetal activity, autonomy and sentience that apparently develop some-
where around the seventeenth week of pregnancy.
The Psychology of Pregnancy
In working through the material before the Commission, I was surprised to
find how little was said about the psychological aspects of pregnancy and the
relation to the parents' — especially the mother's — stake in the issue of that
pregnancy. Fetal development and the mother/fetus relationship were discussed
in predominantly physiological terms, as though the mother's sense of proprie-
torship, responsibility, attachment, and even identification towards the fetus
were, from the ethical point of view, epiphenomenal , and so lacked serious
ethical relevance.
10-24
With this in mind, I set on foot a literature search, assuming that a
body of understanding did indeed exist on this subject, which had somehow been
overlooked and disregarded by commentators on the fetal experimentation issue.
The results were meager. Very little of any substance seems to have been written
on the subject. The only general account that came to my attention was an
interesting and perceptive, but somewhat impressionistic, survey from a psycho-
analytic standpoint by Helena Deutsch; while the psychiatric research literature
in the medical libraries of Chicago brought disappointingly little fresh mate-
rial to light.
Deutsch at any rate has the merit of emphasizing that a woman has a strong
and deep psychological investment in her fetus, even in the case of an unwanted
pregnancy; and that this committment is in no way canceled out by the decision
to terminate the pregnancy by abortion. (On the contrary, the abortion will
normally be an occasion for feelings of grief, guilt, and even self-mutilation.)
None of this should surely be any real surprise, even from the physiological
standpoint, given the radical changes in a woman's hormonal regime associated
with pregnancy. Quite aside from all discussions of the significance of regres-
sion and identification during pregnancy, therefore, we might have expected the
psychological and psychiatric implications of hormonal and other physiological
changes to have attracted more attention than they appear to have done.
On the level of common sense and common knowledge (or "old midwives ' tales")
there is, of course, a certain body of inherited folk-wisdom about these things.
In maternity homes for unmarried mothers, for instance, great care is often taken
to prevent the woman from seeing or hearing her baby during delivery, if it is
already earmarked for adoption. It is explained that any sensory contact with
the infant makes for a much more painful separation, and aggravates the psycholo-
gical impact of the loss. (This belief ties in well with more recent suggestions,
from the direction of ethology, that auditory and/or visual cues may "imprint"
a mother on her infant at birth so that she thereafter, say, recognizes its cry
at once, even against a background of other babies cries.) Yet, once again,
these folk-traditions seem never to have been systematically brought together or
related to any coherent account of maternal psychology during and after pregnancy.
Arguably, these psychological issues form a significant part of the back-
ground against which any questions about the ethics of abortion and fetal research
need to be considered. The whole notion of "risk to the mother" should be treated
as embracing risk of psychological damage; discussions about the parents' state
or investment in the health or survival of an infant, or in the handling and
disposal of a stillbirth or an aborted fetus, should similiarly be taken as
including their psychological stake or investment; and the nature of a mother's
ethical "rights," "responsibilities" and "entitlements," in respect of her issue,
cannot be considered inadequate depth without paying proper attention to the
psychological factors involved.
To repeat, this is not just a matter of the casual or conventional senti-
ments that a woman may express about her condition and offspring. It is a matter
that has to do with one of the two linked aspects of a sequence of changes that
are at once physiological and psychological: one aspect of a process which
could not achieve its natural function unless the anatomical, physiological
10-25
and biochemical developments taking place in the mother and her offspring were
associated with well-matched psychological changes. Considering the striking
manner in which a woman is physiologically prepared to take up her maternal
role — with all its deep emotional and behavioral concomitants — after delivery,
it is clear that significant psychological changes are already in train much
earlier in pregnancy. The Commission would be doing a real service, accordingly,
if it gave its encouragement to a new program for research in this area. At the
very least, it would be a great help to have some sort of a first map of the
different psychological, physiological and hormonal changes characteristic of
the different stages in pregnancy, and their consequences for the mother's sense
of commitment and identification towards her offspring.
(This paper was prepared in collaboration with Donna Boyan and Marilyn Di Salvo,
to whom my thanks are due) .
DETERMINING DEATH AND VIABILITY
IN FETUSES AND ABORTUSES
Leon R. Kass, M.D., Ph.D.
LEON KASS, M.D., Ph.D.
Dr. Kass is presently the Joseph P. Kennedy, Sr.,
Research Professor in Bioethics at the Kennedy
Institute, and Associate Professor of Neurology
and Philosophy at Georgetown University.
PD 304218-5
Determining Death and Viability
in Fetuses and Abortuses
The purpose of this paper is to explore and clarify the notions of fetal
"life," "death," and "viability," and to suggest general principles, standards,
and operational criteria for determining (a) when a fetus (or abortus) is no
longer alive, and (b) when a fetus (or abortus) is "viable." This is, there-
fore, an inquiry both biological and philosophical — not ethical. This paper
will not address the thorny ethical issues of what may and should be done, or
not done, with living or dead or viable fetuses, in utero or out, especially in
biomedical experimentation. These ethical questions cannot be settled merely
by determining whether the fetus is alive or dead, or whether the fetus is viable
or nonviable.
Yet these determinations (of alive or dead, and of viable or nonviable) ,
while not decisive for resolving the ethical questions, are always central to
properly formulating them, sometimes decisively so. For example, if contrary
to fact, it could be demonstrated that a nonviable fetus is in no way different
from a dead one, then the ethical questions concerning experimentation on non-
viable fetuses would be identical to those concerning experimentation on dead
fetuses. Or if it could be shown, again contrary to fact, that the fetus becomes
a distinct, living organism only after birth or only after reaching the stage of
viability, then the ethical issues of experimenting with a previable fetus would
be no different from those raised by experimenting on tissues or organs. Finally,
even after the different classes are distinguished and defined, the proper "class"
identification of each individual fetus will be necessary in order correctly to
formulate the concrete ethical issues regarding its disposition and use. In
short, discussion of the ethical issues, about classes or individuals, can only
begin after the nature of the experimental subject is clarified, for only when
the subject is known can one consider how it may morally be treated.
When the passions hold the reins of debate, as they often have in the
debates about abortion or about research on living fetuses, words tend to lose
their common meaning, as partisans on each side attempt by loose or loaded usage
to hide certain facts or to distort others. But all responsible parties to the
debate on the ethical issues of fetal research should insist on calling things
by their right names and on precisely and carefully distinguishing in speech
those things that are distinguished in fact — and also, on speaking equally
frankly and precisely about those matters which are indistinguishable or even
confused in fact.
11-1
PRELIMINARY CLARIFICATIONS
A. Preliminary Definitions
1. Fetus : The human embryo from conception to delivery, including what is
normally called the embryonic state. (Here I follow the definition given by the
Peel Commission Report.^)
2. Abortus : A whole fetus of whatever gestational age short of term, out-
side the uterus, whether expelled spontaneously or by a medical or surgical pro-
cedure. This definition excludes the placenta, fetal material macerated at the
time of expulsion, and isolated fetal tissues or organs excised from a living
or dead fetus or abortus. (I follow here, but only in part, the definition
given in both the 1973 and 1974 policy guidelines proposed by the U.S. Depart-
ment of Health, Education, and Welfare.^ Two significant departures from that
definition should be noted: (1) By my provisional definition, an abortus is not
necessarily pre- or nonviable; (2) By my provisional definition, an abortus is
not necessarily living. I have made these changes partly because I do not wish
to beg the question that it is my task to explore, namely, that of determining
which abortuses are and are not living, dead, and viable, partly because the
necessary and sufficient distinguishing features of an abortus are that it is
(a) a fetus, (b) whole or intact, and (c) outside the womb.)
3. "Fetus or Abortus": When this phrase is used below, fetus will mean
"fetus in utero," and abortus (as always) "fetus outside," indicating by this
juxtaposition that the statement in which this phrase occurs applies equally
to both.
B. How These Questions About the State of the Fetus are Related — and Unrelated-
to Abortion
Whether the fetus or abortus is alive or not, or is viable or not--and
also the issues raised regarding its possible use in experimentation — are ques-
tions at least to some extent independent of where it is situated and how it is
obtained. A fetus may be dead in utero or alive on the table. A living fetus
can be obtained by spontaneous or by induced abortion, by induced abortion that
is legal or illegal (or moral or immoral) , by induced abortion in which the
mother desires the death of the fetus or by induced abortion (say, for the sake
of health) in which the mother desires that the fetus could be kept alive.
The decision to have an abortion does not turn a living fetus into a dead
fetus. The decision to abort, like the spontaneously occurring "threat" of a
miscarriage, makes the fetus at most a "dying" or "condemned" fetus but not yet
a dead one. The to-be-aborted fetus is still alive. It is abortion, not the
decision, which is the lethal act.
11-2
Yet not all abortions are lethal. Not every abortion necessarily turns a
living fetus into a dead abortus. For example, where abortion is produced by
expulsion or by hysterotomy, some fetuses "survive" -the procedure as living
fetuses (sometimes even viable ones). The very term "abortion" is ambiguous:
does abortion mean only womb-emptying, or does abortion also mean, necessarily,
feticide? In most cases, womb-emptying and feticide go together, but obviously
not in all. It is precisely in those cases where abortion means or effects only
womb-emptying that the procedure issues in living abortuses that can be used
for research. For this reason, "abortion" in this paper will mean only "womb-
emptying. "
C. The Fetus is an Organism
We are concerned here not with the life and death of fetal cells or tis-
sues or organs, nor with the aliveness or so-called "viability" of the same cells,
tissues, or organs if removed from the fetus for transplantation or laboratory
culture. Such parts of an organism may in some cases survive when they are no
longer parts of the organism — but their aliveness or death poses no moral ques-
tion, and demands of us no clear definition of cellular life, death, etc. The
questions of alive or dead and of viable or not viable that we must address con-
cern only the fetus as a whole organism.
While it may be difficult to say, fully or precisely, what the wholeness
of the fetus is, there can be little doubt that it is such a whole, i.e., that
the fetus is an organism — even in utero. Though it is composed of tissue, it
is not merely tissue, unlike muscle or skin or collagen. The assertion that the
fetus is a part of the mother is simply false. It is a different organism, no
matter how dependent it is on the mother. The fetus, in its varying stages, is
a self-developing, self-changing whole, which assimilates and transforms food
supplied by the mother, and grows and differentiates itself according to the
plan encoded in its own DNA. It becomes, on its own and from within, progres-
sively more organized — i.e., possessed of organs that contribute to the mainte-
nance and functioning of the other organs and of the whole. It has a unique
genotype, different from that of the mother and those "parts" of her which are
truly herself and "her own." The fetus is a distinct organism right from its
start.
To say that the fetus is an organism is not to say that it is a person.
This is a question still to be argued about, but not in this paper. But whether
or not the fetus is a person or a fully human, human being, it is, in any case,
a living organism — until it dies or is killed. Further, the fetus (or abortus)
is human at least in the sense that it is of human origin and is (or was) in the
process of becoming a human being if nothing interferes. These facts — and I
think they are indisputable — are presupposed when one asks for criteria for
determining fetal "life," "death," and "viability," and when one raises ques-
tions about the status of a fetus as a fit subject for scientific investigation.^
11-3
D. Alive and Dead, Viable and Nonviable — How are These Terms Related?
The two pairs of contraries — alive and dead, viable and nonviable — are not
synonymous. That this is so will finally be clear only after each of the terms
has been explored and defined, but there is need for their provisional distinc-
tion. As seen in Figure 1, "viable" and "nonvisible" refer to states of a living
fetus or abortus on either side of some watershed (however wide, vague, or ill-
defined it may be, and however we determine its boundaries) that occurs during
the otherwise continuous process of growth and development from zygote to infant
(to adult), the viable fetus having matured "over" the watershed, the non- or
previable fetus being less mature, i.e., not- (yet) -viable. *
— Implantation
"Natural"
Death
Viable
Fetus
Living Fetus
Figure 1. Nonviable and Viable Stages of Fetal Life
Whereas "viable" and "nonviable" refer to and name particular stages of
development, "alive" and "dead" refer to two mutually exclusive conditions of
the organism which are independent of stage of development. The fetus is alive
from fertilization, but, therefore, it can die at any stage. LiJce any living
organism, like any living child or living adult, a living fetus at whatever
stage — nonviable or viable or full term — can die or be Itilled, i.e., can become
a dead fetus (or dead newborn) . The same must be true of the fetus outside the
mother's body, i.e., of the abortus or premature infant (I repeat: How the fetus
got outside the mother is irrelevant for deciding whether or not it is in fact
alive or viable once it is outside) . The nonviable and the viable abortuses are
alive until they are dead,^ and the terms nonviable and viable should be used
exclusively to refer to species of the genus "living fetus" or "living abortus."
We have, then, determined one crucial matter: To say that a fetus or
abortus is pre- or nonviable is not the same as saying that the fetus or abortus
is dead. A dead fetus or abortus is no longer either previable or viable — it is
simply dead. The nonviable abortus will soon be a dead abortus, and a viable
abortus may in fact not survive (it may be killed or it may succumb to respira-
tory distress, just like a newborn or a premature infant), but in order for these
terms to be properly applied to the fetus or abortus, it must then still be alive.
With these preliminaries behind me, I turn to the two main tasks, deter-
mining whether a fetus or abortus is dead, and determining whether a fetus or
abortus is viable. (This choice of focus — on "dead" and "viable" — has been adop-
ted because it is reasonable to say that after fertilization, a fetus is alive
until proven dead, and also to say that a fetus is nonviable until proven viable.)
In discussing both matters, I consider first, some general principles, then spe-
cific standards and operational criteria, both for the abortus and for the fetus
in utero .
II. DEATH OF THE FETUS AND ABORTUS
A. General Principles
To begin with, I repeat that we are concerned with determining whether the
organism as a whole is dead or alive. This task is at once difficult and easy.
Difficult because biology and medicine are not able to give an adequate expla-
nation for, or account of, the "livingness" of living things, or for that mys-
terious occurrence in which a living organism becomes a dead body. What
"livingness" is, and what is responsible for it--these are long and complicated
questions which admit no simple answer. Yet in almost all cases, we are easily
able to distinguish the living from the dead, even if we cannot say in words what
essentially or at bottom lies at the basis of the distinction. The living and
the dead are distinguished by what they do or by what they do not do.
A living organism, unlike a dead one, does or can do one or more of the
following: digest and assimilate food, metabolize, grow, respire, circulate
its blood, eliminate waste, move itself, receive and respond to outside stimuli,
experience its aliveness. A dead organism can do none of these things, and has
irretrievably lost the ability to perform all these vital activities and func-
tions. Because of these fairly obvious differences between the organism alive
and the organism dead, we can look for functional standards and criteria to
determine that an organism has died, without first struggling to discern what
death itself, or aliveness itself, are.^
The first and major principle, then, for determining fetal death and fetal
aliveness is this: since the fetus is an organism, one should try to evaluate
its aliveness or deadness as one would any other mammalian organism, human or
not, namely, by taking as the standards the presence or absence of certain most
11-5
vital organismic f unctionings. To the extent to which they are applicable, the
same operational criteria should be used for determining these functionings in
the fetus or abortus as in the newborn or the adult.
B. Standards and Criteria for Determining That a Fetus or Abortus Has Died
There has been a movement in recent years to revise the criteria for the
determination of death in adults, occasioned by the advent of life-sustaining
technologies that render questionable in some cases the value of certain vital
signs as genuine signs of life — e.g., heartbeat.' There has been a tendency —
very much in error, in my opinion — to call these new criteria, "criteria of
brain-death," even though they necessitate that functions of organs other than
the brain be examined (e.g., spontaneous respiration), and even though they are
intended to permit diagnosis of death not of a brain but of a whole human being.*
Yet, with one notable exception, the new criteria are very much like the old
criteria. And this exception, concerning the heartbeat and other criteria of
circulatory function, is an exception only in cases in which certain life-
sustaining technologies are in use. In ordinary cases, the new and old stan-
dards and criteria are identical.
What are the standards of organismic life? The organism as a whole is
alive as a whole, in some degree at least, if any of the body-wide systems are
functioning on a body-wide basis, to perform the functions of circulation, res-
piration, digestion, excretion, regulation, awareness, responsiveness, motion,
etc. These various activities depend decisively on (1) circulatory and (2)
respiratory and (3) central nervous system function, each of which is in turn
dependent, at least in part, on the other. For example, the ability to breathe
spontaneously requires a mature and functioning respiratory center in the brain
stem, and the functioning of the brain stem in turn requires adequate circulation
of oxygenated blood. Thus, spontaneous circulatory and respiratory functioning
and spontaneous central nervous system activity are the standards for judging
the presence of "life," and any sign of such functioning must be regarded as a
sign of life. Thus, a fetus or abortus will be considered dead if, based on
ordinary procedures of medical practice, it has experienced an irreversible ces-
sation of spontaneous circulatory and respiratory functions and an irreversible
cessation of spontaneous central nervous system functions.
Though medical progress and changes in ordinary medical practice may alter,
in part, the specific operational criteria for evaluating these standard func-
tions, some criteria can be set down which are unlikely to change. These include
(1) spontaneous muscular movement — that is, movement "initiated by" the fetus
or abortus, (2) response to external stimuli, such as touch, changes in tempera-
ture, and stimuli which generally produce pain, (3) presence of reflexes, (4)
spontaneous respiration — that is, respiration initiated by the fetus or abortus,
and (5) spontaneous heart function--that is, spontaneous cardiac contraction and
movement of the blood. The presence of any one of the aforementioned is a sign
that the organism is alive.
The first three criteria are self-explanatory .^ The last two require some
further comment. Respiration is an ambiguous term; it is used variously to refer
11-6
to (1) the expansion of the chest, (2) the effective ventilation of the lungs,
(3) the effective exchange of gases between lung alveoli and the blood, or (4)
the effective exchange of gases in the various tissues of the body (which may
be obtained by perfusion with oxygenated blood, in the absence of lung function) .
By spontaneous respiration I here mean only (3) the effective exchange of gases
between the lungs and the blood. Thus, while the fetus in utero does make, and
the nonviable abortus may make, so-called "respiratory movements," neither has
spontaneous respiration, and hence both lack this sign of life. Nevertheless,
these very same spontaneous movements, and the "effort" to expand the chest even
when the lungs are not yet inflatable, are fetus- or abortus-initiated movements,
and are on that ground signs that the fetus or abortus is still alive, even if
it will soon be dead. The effort to "breathe," to expand the chest, is a vital
sign even though it is not respiration. It reveals the presence of a function-
ing nervous system acting "at a distance" on a functioning part of the musculo-
skeletal system.
Spontaneous heart function, in the absence of external assistance to induce
or maintain respiration, must be regarded as a sign of life. By heart function,
I mean more than the palpable beat of the heart and certainly more than electri-
cal activity of the heart. I mean a functioning, beating heart causing blood to
flow through the peripheral blood vessels, producing pulses in the arteries.
The unassisted circulation of blood in the fetus or abortus is a sign of organ-
ismic and not merely cellular life. In the absence of spontaneous respiration,
say in the case of a nonviable abortus (e.g., 16 weeks), this circulatory activ-
ity will soon cease, 'and with it or shortly thereafter, all other signs of
organismic life. Spontaneous heart function may, therefore, serve as the last
and least sign of organismic life in the organized and aborted fetus.
In children and adults, the usefulness of pulse and heartbeat as signs of
life is reduced only in those cases in which cardiorespiratory function is arti-
ficially and mechanically sustained — e.g., in a case of a comatose, unresponsive,
and areflexive patient on a respirator whose heart beats "spontaneously" but only
because of the presence of artificial, externally driven respiration. There has
been much discussion of whether or not such a patient is indeed already dead or
whether, instead, he is not yet dead but becomes very quickly dead once the res-
pirator is turned off. This question does not admit of easy resolution. An
identical question may come up in determining the status of circulation as a
sign of life in those intact abortuses whose aliveness is sustained (i.e., whose
dying is prolonged) by external support (e.g., with perfusion). But this com-
plication will not arise initially in determining whether the intact abortus, as
delivered, is alive or not. Spontaneous circulation is a sign of life in the
newly delivered or expelled abortus, even in one that is incapable of respiring
on its own, and even, therefore, in one that cannot sustain this circulatory
functioning on its own for very long.
Should the guidelines for fetal research permit the use of artificial
devices to support the life of such a fetus (i.e., one with spontaneous circu-
lation but no spontaneous respiration) , say by providing gaseous exchange through
a heart-lung-type machine, the circulation of blood in the fetus, and its pulses
and its heartbeat, will no longer remain reliable signs of life, just as they are
not reliable signs of life in a dying adult who is on a respirator or on a
11-7
heart-lung machine. The assisting machinery would have to be disconnected and
the abortus examined to see if spontaneous circulatory function were still pres-
ent. If it were, the fetus would still be regarded as living.
To sum up: For the fetus outside the uterus, life is present if there are
any signs — i.e., if there is even only one sign — of spontaneous circulatory,
respiratory, or central nervous system (brain and spinal cord) fxmction. The
satisfaction of any one of the five criteria mentioned above is a sign that the
abortus is not dead. Fetologists and pediatricians, now and in the future, may
wish to add to and enlarge this list of criteria, so that even in the absence of
all five of the criteria, there may be deemed to be present organismic life.i°
But any one of the above five would be sufficient for determining aliveness, and
their complete absence is necessary — even if not finally sufficient — to declare
an abortus dead.
C. The Fetus In Utero
The foregoing standards, readily applicable to the abortus, apply equally
to the fetus in utero, although they may be harder to evaluate. The fetus
in utero is, of course, not accessible to direct physical examination. Also, as
long as it remains in utero, it will never reveal whether it is capable of spon-
taneous respiration. Before quickening or before the time when fetal heart tones
may be heard (audible using the Doppler principle by about 12 weeks) , the diag-
nosis of fetal death must be made indirectly, by means of various laboratory
tests, and it is often difficult. Regardless of the stage of pregnancy, the
diagnosis of fetal death in utero usually requires more than one examination.
The difficulty of diagnosing fetal death in utero is not a problem perti-
nent only to fetal research; it concerns obstetricians (and patients) generally
in ordinary prenatal obstetrical practice. And while the standards of "aliveness"
and "deadness" to be tested for will remain the same, it is likely that new
techniques for making these diagnoses in utero will be forthcoming in the near
future. Thus, the Commission ought not to rigidly specify the tests needed to
diagnose fetal death in utero, but should leave it up to the evolving procedures
of ordinary obstetrical practice to provide the most reliable indicators.
Common sense does dictate one clear presumption concerning the fetus
in utero: Once the diagnosis of pregnancy has been made, the fetus in utero is
presumed to be alive until proven dead. The burden of proof rests on showing
that fetal death has occurred. This applies equally to the fetus about-to-be-
aborted: such a fetus is to be considered alive at least as long as it remains
within or connected to the mother, unless clear proof of fetal death can be
obtained. (After separation, the abortus can be examined for signs of life.)
These presumptions of aliveness will be correct in almost all cases (except,
perhaps, in cases of threatening spontaneous abortion), and have the added advan-
tage that no living fetus will be mistaken for a dead one.^^
11-8
D. The Fetus During Induced and Spontaneous Abortion
During spontaneous abortions or induced abortions likely to produce an
intact abortus by expulsion, the fetus-becoming-abortus should be presumed alive
until examination of the expelled abortus reveals it to be dead.
If abortion is done by hysterotomy, the finite transition between the fetus
inside and the fetus outside will be directly observable. Under these circum-
stances, the diagnosis of fetal aliveness should be easy, a pulsating umbilical
cord being a clear sign of spontaneous fetal circulation. In such cases, I sug-
gest that the fetus is to be considered alive until (a) it is killed in situ by
the surgeon, 12 or (b) the cord is cut and the separated abortus is examined and
found to lack all five of the above criteria of "aliveness."
E. The Fetus at Very Early Stages
The foregoing standards will make it possible to decide the status of most
if not all fetuses and abortuses that may now be considered as possible subjects
for research. Regarding research on the intrauterine fetus, all fetuses in utero
are presumed alive until proven dead or killed during abortion. Research on the
intact abortus usually contemplates an organized fetus, usually age 13 weeks or
more — since first trimester abortions, done by dilatation and curettage or by
suction, do not yield abortuses fit for whole-abortus research. Thus, the cri-
teria for "life" and death" proposed in this paper are adequate to the main task,
based as they are on those signs of organismic life which are present in an
organized fetus — minimally, in a fetus with an intact circulatory system. These
criteria would, however, be difficult to apply to an abortus "delivered" in the
very early stages of fetal life, especially prior to the differentiation of the
great organ systems. Clearly, a blastocyst or two-week-old embryo is alive, but
not by any of the aforementioned criteria.
There is no point at present in going ahead to try to elaborate criteria
for organismic aliveness and deadness for these early stages. However, it is
worth noting that the criteria here given may need to be supplemented or altered
in the future, especially when and if (1) new methods of early abortion (e.g.,
prostaglandin expulsion) appear which yield intact and obviously living embryos
which by the above criteria will not be identified as alive, or (2) in vitro
fertilization and laboratory growth of early human embryos is perfected, able to
produce partially differentiated and growing organisms in laboratory culture.
III. VIABILITY OF THE FETUS AND ABORTUS
A. Viable — An Ambiguous Term
Before considering standards and criteria for distinguishing the viable
from the nonviable fetuses and abortuses, we need to clarify certain confusing
11-9
and misleading ambiguities in the term "viability."^" The term "viable" can refer
to a present state and its capacities or can denote a prediction of the future.
Someone might say that a healthy newborn baby, if abandoned by its parents, is
not viable, and the same might be said of the child who falls unnoticed off the
ocean liner and who cannot swim, or of the man who contracted bulbar polio in
the days before the iron lung. In all these cases, the use of "not-viable" is
meant as a prediction; one means to say that the now living being will not con-
tinue to live, i.e., is certain to die and soon. is
These predictions about the future are of course related to the current
state of the organism and its current environmental circumstances. The discovery
of the abandoned baby by loving foster parents, the unexpected and prompt arrival
of a rescue party, and the invention of the iron lung could keep the above three
people alive, i.e., render them again viable, "likely to live."
These examples reveal something fundamental about this meaning of
"viability." Viability, in this sense, is determined by the relation of the
individual organism and its environment. Whereas the aliveness or deadness of
the organism can be discerned by examining the organism alone, viability can be
discerned only by considering both the organism and its environment. Changes in
environment, and for our purposes, especially changes in technology, may render
a nonviable organism viable, and vice versa. Both the man with polio and the
15-week-old abortus are unable to breathe on their own. The development of the
iron lung made the first man viable; a comparable future technological develop-
ment, say an artificial placenta able to sustain the fetus to 28 weeks, could
enable today's nonviable fetus to become viable.
Yet there is a second meaning of "viability" that is not relational. There
is a noticeable difference between the man needing an iron lung and- the 16-week-
old abortus. The former has lost the ability to function on his own as a self-
sustaining whole, whereas the latter has never reached that state, and moreover,
cannot at present be brought to that stage. There is a developmental immaturity
in the 16-week old abortus which makes it intrinsically nonviable, and, it is
also incapable of bringing itself or of being brought to the maturational stage
of viability with presently available technology.
This more technical sense of "viable," referring to an achieved stage of
maturity, is of prime importance for our present purpose. Though we must remem-
ber that future technologies may enable a nonviable abortus to be brought alive
to this stage of viability entirely artificially — paralleling the way in which
the fetus in utero normally attains viability on its own, with the "aid" of
maternal nourishment and protection — this stage of viability can be defined, at
least formally, in an unambiguous and nonrelative way, as the stage at which
(and after which) the fetus (or abortus) is able to function as a self-sustaining
whole outside of the mother's body (and outside of an artificial womb). In
practice, it may be rather difficult to say which fetus has reached this stage
and which has not, especially during the twilight period between 20-28 weeks —
and I shall discuss this problem shortly — but what it is we are seeking when we
seek signs of viability should now be clear: the intrinsic ability to function
as a self-sustaining whole outside the womb.^^
B. The Nonviable Fetus and Abortus: Two Distinct Classes
If a fetus with this ability is a viable fetUs, what is a nonviable fetus?
Are nonviable and previable the same thing? The terms are often used inter-
changeably— and there is at present no good reason for not doing so--in refer-
ing to the abortus, although the term "nonviable" invites some to think "dead"
rather than living-but-previable . But there is need for further clarification.
The Peel Commission Report defines a previable fetus as follows: "one
which, although it may show some but not all signs of life, has not yet reached
the stage at which it is able, and is incapable of being made able, to function
as a self-sustaining whole independently of any connection with the mother."
This definition mentions two inabilities: an inability to function indepen-
dently, and an incapacity to be made able to function independently. These two
deficiencies are, at least in principle, separable. There may be two classes of
fetuses or abortuses below the stage of viability: those that are not-yet-
viable but are able to become or to be made viable (e.g., by some to-be-developed
artificial placenta) , and those that are both not yet viable and not able to
become or to be made viable (by anything) .
I thus distinguish three classes, as follows:
1. Viable (fetus or abortus): Able to function as a self-sustaining
whole outside the womb. A viable abortus is thus nothing other
than a premature infant.
2. Previable : Not yet able, but able to become or to be made able,
to function as a self-sustaining whole outside the womb; in
other words, the potentially viable.
3. Not-at-all-viable : Not yet able, and not able to become or to
be made able, to function as a self-sustaining whole outside the
womb. This state and only this state carries the prediction of
certain and imminent death.
If one considers only the extrauterine abortus, today's technology is such
as to render the "previable" a null class. The abortus is either viable or not-
at-all-viable (not withstanding the difficulties we may have in determining which
it is, in some cases). But when we consider all fetuses — both inside and out —
we see that we have, even now, all three classes before us. For, so long as the
fetus is alive in the uterus, connected to the maternal circulation, it is capa-
ble of being brought to the stage of viability, no matter what its age; it is
hence "previable" in the sense defined above. These distinctions are made clear
in the following table.
Table 1. Condition of Fetus at Varying Ages as a Function of Place
Location
Age of Fetus In Utero If Taken Out
12 Weeks Previable Not-at-all Viable
24 Weeks Previable [Uncertain]
30 Weeks Viable Viable
In utero , all living fetuses are at least previable, because they can "be
brought to viability" if there is no abortion. Whether, for purposes of formu-
lating the ethical questions of experimentation on fetuses, these previable
fetuses are to be considered more like the viable or more like the not-at-all-
viable is a matter to be considered. Still the previable intrauterine fetus
becomes not-at-all-viable only upon removal — and not until removal, even when
removal is planned. I hold no particular brief for my terms "not-at-all-viable"
and "previable," though I do think they point to a factually significant, and
probably morally significant, difference between two classes of not-yet-viable
fetuses. Moreover, development of new life-sustaining technologies for extra-
uterine fetuses — e.g., some kind of artificial placentas — may render previable
some, and eventually, perhaps, even many, abortuses that are, at present, not-
at-all-viable. "
The distinction of the two kinds of nonviability enables us to discern
clearly the difference between the broader and narrower meanings of "viable."
The class of fetuses that are "viable" in the broad sense of "savable" or "sal-
vageable" or "likely to live" comprise (a) the viable in the technical sense and
(b) previable, i.e., those able to become or to be made viable. Only the not-
at-all-viable are not savable. I thus suggest the following precise classifi-
cation:
Table 2. Precise Classification of Fetuses
The Salvageable Fetus or Abortus The Not-Salvageable Fetus or Abortus
The Viable The Not-at-all Viable
The Previable
It would seem that the relevant distinction for moral purposes is between the
salvageable and the not-salvageable, not between the viable and the nonviable.
Indeed, in considering the ethics of experimentation, I would treat all intra-
uterine fetuses as members of the same class, the salvageable, including those
for whom abortion is planned. That is, I would urge that the guidelines formu-
lated for research using the previable fetus be governed by the same principles
that govern the guidelines for research using the viable fetus, or in yet other
words, that all intrauterine fetuses are to be considered as equals for the
purposes of experimentation.
Still, the question can be raised, "When a decision to abort is made by the
mother, does not the previable fetus immediately become a not-at-all-viable fetus,
by virtue of that decision?" I think not. Because any decision for abortion can
be reversed up \intil the procedure is begun, because the woman may miss the
scheduled date for the D S C or her doctor may become ill or die, even en route
to the operating room, I would urge that the previable fetus in utero be regarded
always as previable, and hence as potentially viable, even after the decision has
been made for abortion. Only when the abortion procedure itself has begun, and
there is no turning back, can we regard the intrauterine previable fetus as a
not-at-all-viable fetus (though it is then still alive until it in fact dies) .
C . standards and Criteria for Viability
A viable fetus is one which manifests spontaneous circulatory, respiratory,
and central nervous system functioning. Whereas the diagnosis of "aliveness"
entails the presence of any one of the five criteria listed above, the diagnosis
of viability requires the presence of all of these criteria: spontaneous move-
ment, responsiveness, reflexes, spontaneous circulation, and spontaneous res-
piration. As the ability to inflate the lungs and to engage in effective
exchange of gases between lungs and blood is the last of these abilities to be
acquired in normal development, it can serve as the best single guide. And
since there is at present no means to inflate and make even partially functional
the uninflatable lungs of a not-yet-viable fetus, the presence or absence of
spontaneous respiration is a clear, unambiguous, and decisive criterion. This
applies, of course, only to the extrauterine fetus, i.e., abortus. In utero,
it is not possible to prove whether the fetus would or would not be capable of
spontaneous respiration if brought outside. Still, in the abortus, spontaneous
respiration is a significant sign of viability, and, along with the others men-
tioned, constitute the suggested operational criteria.
Some comment should be made about other criteria now used to determine
viability: gestational age, body weight, and crown-rump length. Though
these criteria may be useful, they offer no assurance, and in some cases, can
be misleading. Gestational age is notoriously difficult to determine precisely.
The length of the average menstrual cycle of women varies greatly, and the use
of the date of last menstrual period to calculate fetal age, even in women with
regular cycles, may produce a range of uncertainty of up to 3 weeks. (Menstrual
cycle ranges from 21-42 days, ovulation occurring 14 days before menses, and
hence from 7 to 28 days after the date of the last menstrual period.) Moreover,
20 percent of women will have bleeding episodes during the first 20 weeks of
pregnancy which some may mistake for a menstrual period and thus underestimate
how long pregnant they are. Conversely, a missed period may occur prior to the
period in which conception occurs, thus leading to an inflated estimate of ges-
tational age.
Weight, though obviously much easier to measure accurately, is not always
a good indicator of real gestational age or maturity. Some babies are small for
gestational age, others large. Black babies are, on the average, smaller than
white babies of comparable age; other things being equal, small black babies do
better than small white babies because they are more mature (i.e., older).
Finally, it is not clear how weight should be used as a criterion of viability.
Should one take the weight at which the average fetus can function outside the
womb, or the weight of the smallest fetus ever to have done so? One fetus born
at 395 grams has survived. By retrospective definition, it was viable at that
weight, though no other fetus at that weight has been.
D. Determining Viability of a Fetus In Utero
This is admittedly difficult to do. Estimates of gestational age of less
than 20 weeks, by history and size of uterus, should clearly permit the diagnosis
of a previable fetus with little or no likelihood of error. The diagnosis of
viability can be made, presumptively, again with little likelihood of error, if
11-13
by calculating gestational age and uterine size, the fetus appears to be 28 weeks
or older. In between 20 and 28 weeks, there is uncertainty and the likelihood
of error.
In view of this uncertainty, I have no suggestions to make for how one may
accurately diagnose viability or its lack in a fetus in utero , between 20 and
28 weeks gestation. All one can do is to try to develop reasonable criteria for
a presumption of viability. Various courses could be followed, to be determined
in part by a prior decision about on which side to err. For example, in any case
in which abortion is to be performed by hysterotomy or by prostaglandin expul-
sion in a woman pregnant 20 weeks or more, one could argue for presuming the
fetus to be viable, because it just might come out viable. And for the purpose
of setting guidelines for research involving intrauterine fetuses, I would cer-
tainly think the wise and prudent course is to err on the side of never mistaking
a viable fetus for a nonviable fetus. On this principle, I offer the following
criterion of presumptive viability: A heartbeat audible with the fetoscope,
which appears at about 20 weeks of gestational age. This is a clear and, in the
hands of a competent observer, unmistakable sign of fetal life and approximate
fetal age. My suggestion is this: treat every fetus with a stethoscope audible
heartbeat as if it is viable. Some will not be, but none that are will be mis-
taken for not. (This criterion, though more reliable than estimates of gesta-
tional age, will have approximately the same consequences as the criteria
suggested by the Peel Commission: 20 weeks gestation, corresponding to a weight
of approximately 400-500 grams.)
The Peel Commission suggested drawing a fxirther line, on the immature side
of viability — namely at 300 grams — which roughly marks the stage before which
"those parts of the brain on which consciousness depends are, as yet, very poorly
developed structurally and show no signs of electrical activity. "^^ If these
facts are correct, this line may indeed recommend itself to those who wish to
consider not viability or salvageability , but possible awareness and feeling, and
who want to rule out all possibility that the fetus used in experimentation may
"feelingly" suffer in any way as a result. A consideration of accuracy of the
claim and of the merit of this moral concern are beyond the scope of this paper.
Still, as I have more than once suggested, it is not clear which of the lines
that can be drawn should be given decisive weight in arguing the moral issues,
and I therefore mention the line of "as-yet-no-brain- function" as one more pos-
sible morally significant "boundary" in this undeniably continuous process of
growth and development.
IV. RECOMMENDED CRITERIA FOR DETERMINING FETAL DEATH AND VIABILITY
A. Criteria for Determining Death
1. A fetus or abortus will be considered dead, if, based on ordinary pro-
cedures of medical practice, it has experienced an irreversible ces-
sation of spontaneous circulatory and respiratory functions and an
irreversible cessation of spontaneous central nervous system functions.
2. To be declared dead, a fetus or abortus must show an absence of
(1) spontaneous muscular movement, (2) response to external stimuli,
(3) elicitable reflexes, (4) spontaneous respiration, and (5) spon-
taneous heart function--heartbeat and pulse.
3. The presence of any one of the above criteria is a sign that the
fetus or abortus is alive. ■ ■
4. Electroencephalographic examination is not necessary to make the
diagnosis .
5. Once the diagnosis of pregnancy has been made, the fetus in utero
is presumed to be alive until proved dead.
5. During abortions likely to produce an intact abortus, the fetus-
becoming-abortus should be presumed alive until examination of
the expelled or removed abortus reveals it to be dead.
B. Criteria for Determining Viability ' - .,
1. An aborted fetus is to be considered viable if it manifests all five
of the vital signs listed in A-2 above. Spontaneous respiratory
activity is 'a sine qua non of the diagnosis of viability. Weight and
estimated gestational age are insufficient criteria and should not
siibstitute for clinical examination of the abortus.
2. An intrauterine living fetus should be considered previable (i.e.,
potentially viable) before the age of 20 weeks and viable after the
age of 28 weeks.
3. Accurate diagnosis of viability is not possible for the fetus in utero
between 20 and 28 weeks. The presence of a stethoscope-audible heart-
beat should be taken as a sign of presumptive viability.
4. The to-be-aborted fetus, before the heartbeat is audible, should be
regarded as previable, and hence as salvageable, until the abortion
procedure is in progress and cannot be reversed. Only then can the
fetus be regarded as not-at-all viable.
5. Following expulsion or removal of a fetus, adequate time to assess the
presence of life and viability must be allowed before experimentation
can be considered. The diagnosis of viability, where there is likely
to be doubt, should be made by the delivering obstetrician, and then
only if he is not himself likely to be engaged in subsequent experi-
mentation on the abortus.
11-15
REFERENCES
"The Use of Fetuses and Fetal Material for Research: Report of the Advisory
Group," London: Her Majesty's Stationery Office, 1972, p. 2.
"Protection of Human Subjects: Proposed Policy," Federal Register 39
(No. 165): 30648-30657, at 30653, August 23, 1974; and "Protection of
Human Subjects: Policies and Procedures," Federal Register 38 (No. 221) :
31738-31749, at 31747, November 15, 1973. These two publications will be
referred to as the 1974 and the 1973 DHEW guidelines, respectively.
The general use of the terms "experiment" and "experimentation" is often
confused and confusing, thanks to the ambiguity of the terms. At least
two meanings are intended and these are often interchanged. One meaning
refers to the purpose of a procedure or activity, the other to its like-
lihood of success. In its first meaning, "experimental" — usually in the
sense of "scientific" or "investigational," i.e., for the purpose of
gaining new knowledge — is opposed to "therapeutic," This distinction is
ethically important because it points to the problem of who will benefit
from the procedure, of whose purposes are served. In its second meaning,
"experimental" — in the sense of "new and untested" or "uncertain" — is
opposed to "usual and tested" or "proven" or "certain." This distinction
(usually applied to procedures having a therapeutic purpose) is ethically
important because it points to the problems of risk and uncertainty, and
thus of weighing risks and of calculating benefits and harms. Throughout
this paper, "experimentation" will be taken in the first sense only.
Later in this paper the class "nonviable" will be shown to contain two
distinct subgroups, which I call the "previable" and the "not-at-all-viable. "
To say "dead nonviable" fetus or "dead viable" fetus seems strange, and points
up a source of the confusion. To speak precisely, we should say that the
former is a dead fetus or abortus that died before it had reached the
maturational stage of viability, the latter a dead fetus or abortus that
died after it reached that stage. But the dead nonviable or dead viable
fetuses are not any longer nonviable or viable; they are simply dead — a
proof: it would make no sense to reverse the adjectives and speak of a
"viable dead" fetus. This is why I urge that the terms "nonviable" and
"viable" be reserved for living fetuses only.
To be sure, in some cases, it may be difficult to find out whether or not
the fetus has reached the stage of viability, and one may never know, even
retrospectively, about a 20-28-week-old abortus that fails to survive, since
the death of the abortus need not have been due to its failure to attain the
viable stage. I return below to this problem of uncertainty in my discussion
of "viability. "
11-16
REFERENCES (Continued)
6. The distinction between "standards" and "criteria," and between these and
the more general "concept" of death on the one hand, and the more specific
"tests" and "procedures" on the other hand, have been elaborated in an
article by Alexander M. Capron and Leon R. Kass , entitled, "A Statutory
Definition of the Standards for Determining Human Death: An Appraisal
and a Proposal," University of Pennsylvania Law Review 121: 87-118, 1972),
the relevant pages of which are reproduced in an appendix to this paper.
7. See, for example, "A Definition of Irreversible Coma: Report of the Ad Hoc
Committee of the Harvard Medical School to Examine the Definition of
Brain Death," Journal of the American Medical Association 206: 337-340,
1968; and "Refinements in Criteria for the Determination of Death: An
Appraisal," (A Report by the Task Force on Death and Dying of the
Institute of Society, Ethics, and the Life Sciences) , Journal of the
American Medical Association 221: 48-53, 1972. This is perhaps a good
place to emphasize that the determination of death is a matter absolutely
distinct from a second important question with which it has often been
confused, namely, "When is it permissible to allow a patient, still
alive, to die?" Here the question is, "When is the (ex) patient dead?"
8. This commits the fallacy of confusing the whole with its albeit superior
part. See Capron and Kass, op. cit. , p. 112.
9. See description in "A Definition of Irreversible Coma," cited in reference 7.
10. See section below on death in the fetus at very early stages.
11. That some dead or dying fetuses may be mistaken for living fetuses does not
pose any grave ethical questions, but does raise significant problems
for the interpretation and significance of any scientific research that
might be done using these fetuses and abortuses. Indeed, on purely
scientific grounds, one might question the value of at least some kinds
of experiments that have been done on fetuses prior to and during abortion
procedures, because the experimental subjects may have already been dying
and in very unphysiological states, thus rendering doubtful any inference
that might be drawn from the data about normal fetal physiology or
metabolism.
12. By my understanding of the opinion of the Supreme Court in Roe v. Wade,
such an action would not be legally culpable as manslaughter or murder,
since the Court held that the fetus in utero is not legally a person.
13. The reader is reminded that the definition of "abortus" in this paper
differs from the more usual definition given by obstetricians or by the
DHEW guidelines. Here, abortus means any extra-uterine fetus expelled
by spontaneous or induced abortion, nonviable and viable. Usually,
abortus means only an expelled nonviable fetus.
REFERENCES (Continued)
14. We have already dealt with the confusion caused by assuming that "viable"
is a synonym for "alive." All viable fetuses are living, but not all
live fetuses are viable.
15. Without this qualification of "and soon," the term "nonviable," in this
meaning, would apply to all of us, all of the time.
16. My definition is the same as that used in the Peel Commission Report. It
differs slightly from that used in the DHEW guidelines. The latter, in
both the 1973 and 1974 versions, add the phrase "given the benefit of
available therapy," and imply that viability is in part a function of
available technology (a broader sense of "viability" than mine) . Also,
both versions of the DHEW guidelines speak about procedures that would
terminate the respiration of an abortus (by their definition, nonviable),
yet one would have been led to believe that a nonviable fetus or abortus
has no respiration. The DHEW guidelines are thus confusing on the
matter of viability.
17. I am not suggesting that the presence of new technologies permitting
doctors to prolong the life of nonviable fetuses and abortuses to the
point of viability would make the use of such technologies obligatory
on all or even any nonviable abortus. But the availability of such
life-saving technologies would undercut one ground some people use to
justify research on previable fetuses, namely, that they are necessarily
going to die anyhow, that there is no way to avoid their death. Other
possible justifications, those not dependent on the inevitable and
imminent death of the fetus, would, of course, not be so undermined. I
do not here argue which, of any, of such proposed justifications are now
adequate, and for what kinds of research.
18. The Peel Commission Report. "
19. Quotations from or other uses of this paper require permission of the author.
IV. What Can and Should Be Legislated?
Arguments both for and against the desirability of legislation "defining"
death often fail to distinguish among the several different subjects that might
be touched on by such legislation. As a result, a mistaken impression may exist
that a single statutory model is, and must be, the object of debate. An appre-
ciation of the multiple meanings of a "definition of death" may help to refine
the deliberations.
Death, in the sense the term is of interest here, can be defined purely
formally as the transition, however abrupt or gradual, between the state of being
alive and the state of being dead.^^ There are at least four levels of "defi-
nitions" that v/ould give substance to this formal notion; in principle, each
could be the subject of legislation: (1) the basic concept or idea; (2) general
physiological standards; (3) operational criteria; and (4) specific tests or
procedures .5^
The basic concept of death is fundamentally a philosophical matter.
Examples of possible "definitions" of death at this level include "permanent
cessation of the integrated functioning of the organism as a whole," "departure
of the animating or vital principle," or "irreversible loss of personhood."
These abstract definitions offer little concrete help in the practical task of
determining whether a person has died but they may very well influence how one
goes about devising standards and criteria.
In setting forth the general physiological standard (s) for recognizing death,
the definition moves to a level which is more medicotechnical , but not wholly
so. Philosophical issues persist in the choice to define death in terms of organ
systems, physiological functions, or recognizable human activities, capacities,
and conditions. Examples of possible general standards include "irreversible
cessation of spontaneous respiratory and/or circulatory functions," "irreversible
loss of spontaneous brain functions," "irreversible loss of the ability to
respond or communicate," or some combination of these.
Operational criteria further define what is meant by the general physio-
logical standards. The absence of cardiac contraction and lack of movement of
the blood are examples of traditional criteria for "cessation of spontaneous
circulatory functions," whereas deep coma, the absence of reflexes, and the lack
of spontaneous muscular movements and spontaneous respiration are among criteria
proposed for "cessation of spontaneous brain functions" by the Harvard Committee.
Fourth, there are the specific tests and procedures to see if the criteria
are fulfilled. Pulse, heart beat, blood pressure, electrocardiogram, and exam-
ination of blood flow in the retinal vessels are among the specific tests of
cardiac contraction and movement of the blood. Reaction to painful stimuli,
appearance of the pupils and their responsiveness to light, and observation of
movement and breathing over a specified time period are among specific tests of
the "brain function" criteria enumerated above.
There appears to be general agreement that legislation should not seek to
"define death" at either the most general or the most specific levels (the first
and fourth). In the case of the former, differences of opinion would seem hard
to resolve, and agreement, if it were possible, would provide little guidance
for practice. In the case of the latter, the specific tests and procedures must
be kept open to changes in medical knowledge and technology. Thus, arguments
concerning the advisability and desirability of a statutory definition of death
are usually confined to the two levels we have called "standards" and "criteria,"
yet often without any apparent awareness of the distinction between them. The
need for flexibility in the face of medical advance would appear to be a persua-
sive argument for not legislating any specific operational criteria. Moreover,
these are almost exclusively technical matters, best left to the judgment of
physicians. Thus, the kind of "definition" suitable for legislation would be a
definition of the general physiological standard or standards. Such a definition,
while not immutable, could be expected to be useful for a long period of time
and would therefore not require frequent amendment.
University of Pennsylvania Law Review 121: 102-103, 1972.
57. For a debate on the underlying issues see Morison, Death: Process or
Event?, 173 SCIENCE 694 (1970); Kass, Death as an Event: A Commentary on Robert
Morison, 173 SCIENCE 698 (1971).
58. To our knowledge, this delineation of four levels has not been made
elsewhere in the existing literature on this subject. Therefore, the terms
"concept," "standard," "criteria," and "tests and procedures" as used here bear
no necessary connection to the ways in which others may use these same terms,
and in fact we recognize that in some areas of discourse, the term "standards"
is more, rather than less, operational and concrete than "criteria" — just the
reverse of our ordering. Our terminology was selected so that the category we
call "criteria" would correspond to the level of specificity at which the Ad Hoc
Committee framed its proposals, which it called and which are widely referred to
as the "new criteria" for determining death. We have attempted to be consistent
in our use of these terms throughout this Article. Nevertheless, our major pur-
pose here is not to achieve public acceptance of our terms, but to promote aware-
ness of the four different levels of a "definition" of death to which the terms
refer.
11-20
12
REPORT ON VIABILITY AND NONVIABILITY
OF THE FETUS
RICHARD E. BEHRMAN, LL.B., M.D., and
TOVE S. ROSEN, M.D.
Principal Investigators
Dr. Behrman is presently Professor and Chairman of
the Department of Pediatrics, College of Physicians
and Surgeons, Columbia University.
Dr. Rosen is Assistant Professor of Pediatrics, College
of Physicians and Surgeons, Columbia University.
NO1-HU-5-2120
Contents
INTRODUCTION 12-1
DEFINITIONS 12-1
CHANGES IN SURVIVAL RATES 12-2
A. Sources 12-2
B. Limitations 12-2
C. Weight and Gestational Age Classifications and Survival 12-3
D. Survival Trends for Premature Infants by Weight Groups 12-3
E. Special Problem of the Discrepancy Between Prenatal
Prediction of Fetal Age and Weight and the Postnatally
Measured Weight of a Premature Infant 12-8
F. Summary of Case Reports of Survivals at Less Than 601 Gram
Weight or at Gestational Age of 24 Weeks or Less 12-9
G. Quality of Survival 12-11
CHANGES IN MEDICAL TECHNOLOGY AND CARE OF THE PAST DECADE 12-13
A. Introduction 12-13
B. Sources 12-13
C. Limitations ' 12-13
D. Overview 12-14
E. Major Changes in the Technology and Care of Premature
Infants 12-15
F. Potential Areas for Medical Advances Directly Related to
the Care of Premature Infants Which May be Dependent in
Part on Investigation of the Human Fetus and Premature
Infant During the Next Decade 12-24
FORMULATION OF GUIDELINES FOR PHYSICIANS 12-25
A. Viability and Nonviability .. 12-25
B. Fetal and Premature Infant Death ; 12-27
C. Options and Their Implications for Premature Infants 12-27
BIBLIOGRAPHY 12-31
APPENDIX A 12-49
APPENDIX B 12-59
APPENDIX C 12-109
Report on Viability and Nonviability
of the Fetus
INTRODUCTION
This report is organized into four sections:
1. Definitions
2. The changes that have occurred over the past ten years in
survival rates, particularly weight specific survival rates
3. The changes in medical technology and care during this
period, including an assessment of the present state of
technology and medical care relevant to improving survival
for premature infants
4. Based on 2, 3, and present medical understanding, a formu-
lation of possible guidelines for use by physicians in
determining whether a fetus, delivered spontaneously or as
a result of an induced abortion is viable, nonviable or
dead. Some of the implications for newborn infant care of
various interpretations of the biologic data will also be
indicated.
1. DEFINITIONS
The Fetus : the human embryo from conception to delivery. (As in the
"Peel Report" and the preliminary Mahoney report to the Commission,
no distinction is made between embryonic and fetal periods of intra-
uterine development.)
The Premature Infant; The human fetus after delivery that weighs less than
2500 grams (5-1/2 lbs.) is not born dead, and is judged by a physician
in attendance to have a chance of surviving despite low weight and/or
gestational age. Thus, a stillborn or deadborn infant and a 100-gram
prematurely delivered infant are not counted in determining the inci-
dence of prematurity or premature survival rates.
Fetal Death: (1) The death of a product of conception prior to complete
expulsion or extraction from the uterus, or (2) the death of a product
of conception expelled from the uterus, judged to have no chance of
survival at delivery because of low weight or gestational age. Thus,
12-1
a stillborn or deadborn infant and a premature infant judged not to
have any chance of survival because of its low weight and/or gesta-
tional age may be included as a fetal death for official recording
purposes. In some instances stillborn infants are recorded separately.
Inborn Infant: An infant delivered in the hospital where the infant is
receiving neonatal care.
Outborn Infant: An infant delivered in a hospital other than that where
the infant is receiving neonatal care.
Neonatal Infant: An infant of less than 28 days of life for most recording
purposes. However, commonly used to include infants up to six weeks of
life who may, if sick, be cared for in Neonatal Intensive Care Centers.
2. CHANGES IN SURVIVAL RATES
A. Sources . A survey was made of the English literature, vital statistics
for the United States and the Canadian province of Quebec, selected vital statis-
tics of individual states and unpublished or partially published data from 27
major centers with obstetrical services and special intensive care units for pre-
mature units.
B. Limitations ■ The United Nations and the U.S. Census Bureau estimate
the world population at approximately 3,860,000,000. Using the estimate of
32 births per 1,000 population of 1972, there are approximately 123.5 million
births per year in the world. There are approximately 3 million births in the
United States which represent less than 3 percent of the total world's births.
The weight specific survival data and related information are obtained from a
relatively small subset of the births in the United States and Canada selected
on the basis of availability and the time constraints of the Commission's report.
This does not represent a statistical sampling of the total world births, U.S.
births or Canadian births over the ten-year period. Each of the medical centers
whose data are presented accepts premature infants referred for care after
delivery elsewhere (outborn) as well as infants delivered at the center itself
(inborn). Data were not available in the U.S. on the total number of deliveries
in each area from which the hospitalized infants are drawn and the fraction of
this total number which the delivery of these infants represents. Such data were
available for Quebec and one center in Montreal. Since a true estimate of prob-
ability of survival depends on this information, only crude estimates of weight
specific survival probabilities were possible.
Most of the world, national and state information on births that is col-
lected makes no attempt to record data on premature infants by small weight
increments; rather, all infants less than 2500 grams and/or less than 1000 grams
are grouped together. There is also an uncertain area where premature deaths
and fetal deaths tend to merge for recording purposes . Depending on local custom
and laws , this area is usually about 500 grams , but may on occasion range between
500 and 1000 grams.
The most reliable quality data for weight specific survival were obtained
from the province of Quebec in Canada and from a number of individual neonatal
intensive care centers and obstetrical services in the United States. It is in
these medical centers that the most advanced technology and care have been
applied during the past decade. It is potentially possible in these centers to
evaluate the effect of changes on survival of premature infants that cannot be
detected for city, state or national populations. Using regional and state data
it is difficult to evaluate the beneficial or adverse effects of changes in care
because of the inclusion of large numbers of low-risk premature infants of birth
weights of 1500-2500 grams.
Data from selected neonatal intensive care centers are provided in
Appendix B. These data are limited because not all centers had information
available for a ten-year period. Most had to review and organize their data
especially for the Commission, giving priority to providing data at small incre-
ments for low birth-weight groups. ■ ..
C . Weight and Gestational Age Classifications and Survival . Up to the
present almost all of the information available relating weight to gestational
age during fetal life has been based on correlating the weights of the products
of conception after they have been delivered (e.g., premature infant, deadborn
or those products of conception not judged to have any chance of surviving) with
estimates of postconception age calculated from menstrual histories (from the
first day of the last menstrual period [LMP] ) . Estimates of gestational age
based on LMP cannot be determined in 15-30 percent of pregnancies. The variation
in estimated gestational ages at different weights is presented in Table 1 (see
Appendix B) . Conversely, on the basis of observations in animals, in human twin
pregnancies, in small groups of women carefully monitored for date of conception
and menstrual history, and from ultrasound studies of fetal length and head cir-
cumference, it also has been established that a substantial variation in weight
may occur at specific gestational ages. The variation in weight at different
gestational ages in centers surveyed in this report is illustrated in Table 2.
The available data relating percent survival to different weight groups or to
different gestational ages should be considered with these variations in mind.
The use of both weight and gestational age together at birth is of clinical
importance in predicting which groups of infants are at increased risk of death
or illness before clinical symptoms or signs develop. However, this use is dif-
ferent than relying upon a prenatal estimate of a "nonviable" gestation age to
predict the likelihood that an infant will, in fact, be born at a "nonviable"
weight (see page 12-7).
D. Survival Trends for Premature Infants by Weight Groups. There are no
national or international data available that provide rates of survival by 250-
gram weight groupings for the past decade. However, such data are available for
New York City and are generally considered to be of high quality by authorities
in the field of public health and epidemiology. Data are collected in a uniform
manner by the Department of Health from all hospitals in the City. From 1962 to
1971 there was a 4.5 percent increase in the survival rate for all premature
infants (infants under 2500 grams) which is equivalent to a 26 percent reduction
in mortality (Table 3) . The improvement in survival of the nonwhite group was
6.9 percent, a 36 percent decrease in the mortality rate. This improvement was
12-3
primarily in infants weighing less than 2000 grains with increases of 68 percent,
20 percent and 6 percent in the survival rates of infants in the under 1000 gram,
1001-1500 gram, and 1501-2000 gram weight groupings; respectively. When the
data available from the thirteen New York City Premature Centers were separately
analyzed (Tables 4-13) , a further improvement in survival of inborn white infants
in these same weight groupings was apparent from 1971 to 1973 for inborn premature
infants, especially for white infants of 751-1500 grams (a 49 percent increase
in survival rate) and nonwhite 751-1000 grams (a 127 percent increase in survival
rate) (Tables 11-13) . Further analysis of the trends in these Centers suggests
that there may have been increases in survival in the outborn white premature
infants in 1954 (1001-1250 gram weight group) and 1967 (in the three weight groups
between 751-1250 grams) , in all outborn infants in 1967 and 1968 and in inborn
nonwhite infants in 1968 and 1969 (in the three weight groups between 751-1250
grams) . For purposes of general comparison over this same period of time the
neonatal mortality in the United States was reduced 24 percent. In Oregon the
neonatal mortality decreased 30 percent and the survival of premature infants of
1001-2500 grams was increased 4.9 percent (a 38 percent decrease in the mortality
rate) (see Table 14) .
(1) Probability for Survival of Infants Weighing Less Than 1001 Grams.
Any estimation of the chance of survival based upon the overall experience in the
United States would need to be calculated from the documented survivors recorded
in case reports and Premature Center statistics compared to the total number of
births per year. On the experience of the past decade this would mean that there
is about one chance in 5-6 million total births of an infant weighing less than
601 grams surviving in the United States. Although based on a large number of
deliveries from census data, the uncertainty that all cases were reported and the
lack of information about the numbers of infants born by weight subgroupings made
us reject this approach in developing a probability table.
Alternatively, if we used the Quebec data to calculate a probability of
survival based on the number of survivors in each 50-gram weight grouping compared
to the total births in each weight grouping, this would lead us to estimate that
there would be no survivors of 551-600 grams. However, this inference would be
based on only 190 births which we consider too small a number of births for cal-
culating a clinically valid probability (Table 15). Therefore, the probability
of survival in each weight group was calculated by a comparison with the total
births in the Province of Quebec during the period studied (276,531).
For the entire province of Quebec from 1970 to 1972 there were 272,445
livebirths. None of those weighing less than 601 grams survived (Table 15). As
the risk of fetal death is lowered, the number of infants born alive will corre-
spondingly increase. Thus, the chance of survival is best expressed in terms of
the number of premature infants surviving per total births (stillborn or deadborn
plus liveborn) . The lowest fetal death rate (percent stillbirths) for all weights
is probably that obtained at the University of California in Los Angeles where
there has been the most extensive experience with ultrasonic monitoring of the
fetal heart rate. This rate was 15 fetal deaths per 1,000 livebirths in 1970 to
1972. Adding these calculated fetal deaths to the Quebec livebirths during this
12-4
period, there were no survivors less than 601 grams out of 276,531 total births
in Quebec. The chances of survival at birth weights above 600 grams were:
Probability of Survival
Birth Weight (grams) Probability of Survival Per Million Total Births
601 -
650
1
in
276,531
3.6
651 -
700
1
in
92,177
10.8
701 -
750
1
in
92,177
10.8
751 -
800
1
in
69,132
14.4
801 -
850
1
in
34,566 ■
28.8
851 -
900
1
in
27,653
36.0
901 -
950
• 1
in
14,554 ■
98.4
951 -
1000
1
in
14,554
98.4
Unfortunately, data are not available in the United States to permit
analysis of the weight specific survival rates in terms of the total number of
deliveries that occurred in the population served by any one of the major pre-
mature referral centers. However, this has been done for the premature center
at the Montreal Children's Hospital. Table 16 shows that no infant weighing
less than 700 grams Survived from 1970-1974 from a total of 85,200 consecutive
livebirths in the referring hospitals. The one survivor in the 701-750 weight
group represents a probability of survival rate of 11.5 per million total
deliveries (when corrected for the fetal death rate) at a neonatal intensive
care center. This is in comparison with the prediction of 10.8 estimated for
the entire province of Quebec, which includes many hospitals without intensive
care units.
The appropriateness of applying this kind of interpolation to the United
States can be evaluated by looking at the data from Stanford University Medical
Center from 1964-1974 (Table 17) , University of Colorado Medical Center, 1963-
1973 (Table 18) , Boston Hospital for Women from 1963-1973 (Table 19) , University
of Minnesota, 1970-1974 (Table 20), and Cincinnati General Hospital, 1973-74
(Table 21) . Of the total number of fetuses and premature infants (inborn and
outborn) in the weight groups below 601 grams cared for in these institutions
there were no survivors. At Stanford there was one survivor who weighed 551-600
grams, but since 1971 there have been no survivors of less than 901 grams. At
Cincinnati General Hospital there was one survivor of 501-550 grams and there
have been no survivors of less than 851 grams since 1973. In Boston there have
been no survivors for the entire period (1963-1973) weighing less than 601 grams.
Similarly, there were no survivors below this weight (Table 22) and few survivors
below 750 grams at the University of California in San Francisco (one survivor
at 601-650 grams) , University of Minnesota (one survivor at 751 grams) , University
of Colorado (one survivor at 851-900 grams) , Tucson Medical Center (one survivor
at 651-750 grams) , or University of Arizona Hospital (one survivor at 651-750 grams)
(Table 23) . Figures 1-3 summarize this information (see Appendix A) . Figure 1
shows the total number of survivors in each weight group. Figure 2 represents this
total number of survivors as a fraction of the total livebirths. Figure 3 illus-
trates the improvement in survival that has occurred in each weight group from
1963-1969 to 1970-1974. The increased number of infants in each weight category
in the more recent period reflects, in part, an increase in prompt regionalized
referrals to these Centers. Many of these infants previously did not survive long
enough to get to these Centers.
12-5
Because of the small numbers of premature infants born weighing less than
1000 grams who are cared for each year in an individual premature center,
survival trends over the past decade may be poorly appreciated when looking at
data reported by a particular center. The survival data for the whole of New
York City for the years 1962-1971 is, however, useful to delineate these trends
(Table 3) . It represents experience with over three times as many infants in
this weight grouping as the experience in Quebec. There was a 68 percent
improvement in survival rate of infants weighing less than 1000 grams during
this period but there were no survivors out of 989 births under 500 grams cared
for in the thirteen premature centers of the City of New York. These centers
care for infants from the entire New York metropolitan area including Westchester,
New Jersey and Long Island. Unfortunately, only 250 gram weight groups are used
so it is only possible to determine the weight distribution of survivors in two
groups: 501-750 and 751-1000 grams.
(2) Probability of Survival for Infants Less Than 28 Weeks Gestational
Age. Four centers had gestational age estimations grouped at two-week intervals
available for analysis: University of California at San Francisco, 1965-1974
(Table 22) , University of Colorado, 1963-1973 (Table 18) , University of Minnesota,
1970-1974 (Table 20) and the Royal Victoria Hospital, 1966-1974 (Table 24). In
no instance did an infant of 24 weeks or less gestational age survive (Table 25) .
The surviving infants of 25 weeks gestation weighed more than 750 grams. Menstrual
histories were generally used to estimate gestational age, although some ages may
have been adjusted to make them compatible with gestational age estimated by
physical examination (see page 12-15) .
Figures 4 and 5 indicate the number and percent of livebirths surviving at
each gestational age. These results are combined in Figure 6.
The results from these centers do not permit a numerical estimate of the
probability of survival for those infants of 25 weeks or greater gestational age
since the total population of births, of which these infants are a small part, is
unknown. By interpolation from Table 2, Table 15 and the total births of the
province of Quebec, an infant of 25 weeks probably has a chance of surviving no
better than 3.6 parts in 1 million.
(3) Changes in Survival at Selected Neonatal Intensive Care Centers.
Changes in survival of premature infants during the past decade also can be
evaluated in terms of the experience prior to the creation of neonatal intensive
care centers and trends in these individual centers over a number of years.
Table 26 suggests a marked improvement in survival of infants of 751-1000 grams
since 1920 and when two more recent time periods were compared at the Royal
Victoria Hospital, Montreal. A comparison of results at this premature center
with those of the province of Quebec is provided in Figure 7 and Table 27. These
results demonstrate improved survival at the borderline of viability but no
survival at less than 25 weeks.
The changes resulting from intensive obstetrical care have been well demon-
strated at the Los Angeles County-USC Medical Center. Here, continuous intra-
uterine fetal heart rate monitoring with ultrasound was initiated on high-risk
12-6
obstetrical patients in 1970 before it was generally accepted in obstetrical
practice. The unmonitored patients were low-risk patients. As the number of
patients monitored increased, the fetal death rate decreased (Table 28). The
intrapartum death rate of infants weighing more than 1500 grams decreased
64 percent from 1970 to 1973. A controlled study was not undertaken, but
Table 29 shows that the fetal death rate was lower in those monitored high-risk
women, who should have had the highest fetal death rate than it was in the
unmonitored low-risk pregnant women. It was also lower than at the Parkland
Hospital (Table 30) of the University of Texas Southwestern Medical School
where special clinical observation but no electrical monitoring was employed
for similar patients. The neonatal death rate at Los Angeles County-University
of Southern California was also decreased in comparison to Parkland (compare
Tables 28 and 30) . The survival of all monitored premature infants at Los
Angeles County-University of Southern California was improved compared to
unmonitored premature infants at the same institution (Table 31) .
Comparable results to those on the West Coast have been obtained at the
Columbia-Presbyterian Medical Center in New York City. Figure 8 summarizes
birth rate and mortality data over the last 20 years at this Center, divided
into five periods. The first period is prior to monitoring. Fetal acid-base
monitoring was begun on a very limited scale in 1953. Fetal heart rate moni-
toring was added in 1958. Both techniques were not used extensively until the
last period. The annual birth rate has fallen considerably from over 4,000 per
year to 3,000, particularly since the introduction of legalized abortion. The
stillbirth rate has not shown any particular trend, but the neonatal death rate
in liveborn infants of 1000 grams or more has fallen from a high of 12.9 per
thousand to a low of 5.8 per thousand, representing a 47 percent improvement.
Although the birth rate has fallen, the incidence of prematurity has remained
approximately the same at about 9 percent. The greatest change in mortality
coincided with the largest increase in the use of monitoring. Perinatal mor-
tality also showed a decrease over the same period. It is of particular impor-
tance to note that 90 percent of the monitoring is done on ward or service (non-
private) patients who are primarily indigent black and Hispanic. A very large
proportion of these pregnancies are classified as being at high fetal and neo-
natal risk compared to the unmonitored private patients. However, the monitored
high-risk nonprivate patients has 10 percent less neonatal deaths, 14 percent
less perinatal deaths (fetal and neonatal) and 37 percent less intrapartum fetal
deaths .
The major trends in survival of premature infants must also be viewed from
the perspective of individual neonatal intensive care centers where there is the
greatest concentration of expertise and technology. The general trend of
decreasing neonatal mortality apparent in the neonatal intensive care units at
Los Angeles County-USC Medical Center and University of Oregon Hospital are
typical for this country (Table 32). When examined by weight groups, consistent
improvement in premature survival in such centers is documented by representative
data obtained from neonatal intensive care units at Denver Children's Hospital
and the University of California at San Francisco (Tables 33 and 34) .
A decreased incidence in the birth of premature infants of 751-1250 grams
in weight may have occurred since the frequency of legal abortions increased
(Table 35) . Data from the center of the University of California at San Francisco
12-7
are particularly illustrative. Both the percent of premature infants surviving
and the intelligence quotient of the survivors have improved over the past decade
(Figure 9) . A difference in survival is demonstrated by comparing the neonatal
mortality at this center with that of the City of San Francisco and the United
States (Figure 10) .
E. Special Problem of the Discrepancy Between Prenatal Prediction of
Fetal Age and Weight and the Postnatally Measured Weight of a Premature Infant.
The only presently used clinical means of estimating fetal weight is based on
the obstetrician's experience in manual abdominal palpation of the uterus. It
is as accurate as any other method that has been proposed which involves ancil-
lary measurements and calculations. The error of the experienced obstetrician
in estimating fetal weight in this manner increases with decreasing weight from
the end of the first trimester through the beginning of the second trimester and
may be greater than 100 percent. Thus, the physician's estimate of the weight
of a 600 gram fetus in utero may be consistent with delivery of a 1000-1200 gram
premature infant.
Fetal gestational age may be estimated from the height of the uterine
fundus; the time of maternal perception of fetal movement (quickening); first
detection of fetal heart tones; roentgenographic evaluation of fetal size, ossi-
fication centers and dispersion of lipid soluble dyes; amniotic fluid analysis
for creatinine phospholipids, bilirubin, osmolarity, electrolytes and cytology;
and measurement of fetal head dimensions with echoes of sound frequencies above
audible levels (ultrasonic cephalometry) . These methods should not be confused
with the estimation of the gestational age of an infant by physical examination
after birth (see page 12-15) .
Ultrasonic cephalometry has been used in clinical human fetal experiments
to determine the relationship of gestational age estimated by last menstrual
period in a number of normal pregnancies (selected for the reliability of men-
strual histories) to the linear head dimensions of the fetus determined by ultra-
sound in these pregnancies. This information is now used to monitor changing
head dimensions during pregnancy as an index of normal fetal growth. This can
help to identify certain abnormalities in the developing fetus for purposes of
initiating prompt treatment after delivery in an appropriate hospital facility
or for purposes of abortion of grossly malformed infants. It is the most accu-
rate method presently available, but at best most experienced clinical investi-
gators believe it has an error of +1 week (+2 standard deviations) from 22 to
26 weeks gestational age (Figure 11) . Several authorities believe this error
to be +2 weeks. The combined use of several of these methods to estimate gesta-
tional age has not demonstrably decreased this error.
The ultrasound technique can also be used as an indirect way of deter-
mining chances of fetal survival: the head dimension of a fetus of unknown or
estimated gestational age (by menstrual history) is measured by ultrasound and
this measurement is equated with a specific gestational age from the aforemen-
tioned series of normal pregnant women whose menstrual histories were considered
to be very reliable. There is, of course, no information relating this gesta-
tional age or the ultrasonic head measurement to the fetal weight at the time
of measurement since all the information is obtained from normal pregnancies
that deliver months after the ultrasonic measurement is made.
One must then relate this estimate of gestational age to a prediction of
survival (page 12-6) or to a weight, which is itself related to a prediction of
survival (page 12-5) . If one relates gestational age to weight, it is seen from
Table 2 that at 24 weeks gestational age the one-week error implicit in the ges-
tational age estimation by ultrasound before birth is consistent with the birth
of a product of conception weighing 500 grams or 1000 grams. There is no chance
of survival if the weight is 500 grams, but a 1000-gram premature infant has
98 chances in 1 million of surviving and would unquestionably be considered
"viable" in current medical practice.
If a legal abortion had been undertaken at the estimated gestational age
of 24 weeks (by ultrasound) , in the above example there would be a definite,
although small, possibility that the woman could be delivered of a 25-week ges-
tation, viable 1000-gram premature infant. If the gestational age before birth
is estimated at 23 weeks, it is extremely unlikely, but possible, that the
product of conception would be of a weight and gestational age associated with
survival. Thus, there are two problems presented here: (1) the problem of the
potential discrepancy between expected weight (and survival) based on the best
available prenatal estimate of gestational age and (2) the actual weight of the
product of conception after birth based on an actually measured weight. In both
instances despite the legality of the abortion and the best prenatal medical
judgment, the outcome of medical management may be contrary to the intention of
the pregnant woman and the physician. In regard to human investigation initiated
after delivery, the subjects can be precisely selected for no probability of
survival by accurate determination of weight after birth. When initiating human
investigation before birth, the same precision in subject selection is not pos-
sible over the entire gestational time period when abortion is legal. At 24
weeks gestation it is not always possible to predict before delivery that the
abortus will be delivered at a weight incompatible with survival because the
abortus may, in fact, be 25 weeks gestational age.
F- Summary of Case Reports of Survivals at Less Than 601 Gram Weight or
at Gestational Age of 24 Weeks or Less (see Appendix C for greater detail) . In
each of the following cases either weight was inappropriately small for the
gestational age or some serious question can be raised about the validity of the
weight or gestational age. In no instance did a reported infant survive who was
both less than 601 grams and of a gestational age of 24 weeks or less. The Apgar
score referred to in the following cases is a clinical system for evaluating the
degree of depression at birth at 1 and 5 minutes. A low 5-minute score (6 or
less on scale of 10) has been established by a national collaborative project to
correlate with a later increased incidence of handicaps , motor and mental abnor-
malities.
Case No. 1
A 580-gram black female infant was born by breech extraction at the University
of Cincinnati Medical Center with Apgar scores of 5 and 8 at 1 and 5 minutes,
respectively. In utero estimation of gestational age was 25-27 weeks. Physical
examination revealed an infant with an estimated gestational age of 24-26 weeks.
During hospitalization she developed severe respiratory distress , diagnosed as
hyaline membrane disease, apnea, bradycardia, sepsis and anemia. Following
12-9
appropriate therapy she was discharged at three months of age at a weight of
2270 grains. On follow-up at 17 months her size was small, physical and neuro-
logical examinations were within normal levels, but developmental milestones were
retarded.
Case No. 2
A 539-gram black female was born at the University of Maryland Hospital by
normal spontaneous vaginal delivery with Apgar scores of 0 and 4 at 1 and 5
minutes, respectively. Physical examination showed a premature normal female
with an estimated gestational age of 28 weeks. During hospitalization she
developed respiratory distress, persistent metabolic acidosis, apnea and sepsis.
She responded to therapy and was discharged at three months of age at a weight
of 2693 grams. On follow-up she has done well, and at two years of age she was
thought to be normal neurologically and developmentally .
Case No. 3
A 580-gram infant was transferred to Colorado General Hospital on day of birth.
The estimated gestation by menstrual history was 29 weeks , and estimated gesta-
tional age on physical examination was 30-34 weeks. The pregnancy was compli-
cated by edema, proteinuria and hypertension. The infant's Apgar scores were
3 and 8 at 1 and 5 minutes, respectively. Infant required endotracheal tube
positive pressure resuscitation. Subsequent feeding activity and neurologic
examinations indicated a mature infant. The child was discharged at 1940 grams
and considered normal at two months of age.
Case No. 4
A 624-gram female infant was born at the University of Arizona at Tucson by
normal spontaneous vaginal delivery. Apgar scores were good. Physical exami-
nation indicated the infant was of approximately 24 weeks gestation. During
hospitalization she developed apnea and congestive heart failure due to a patent
ductus arteriosus which necessitated surgical correction. She also developed
necrotizing enterocolitis. Her weight fell. She is still hospitalized and now
weighs 600 grams.
Case No. 5
A 397-gram female infant was born in Canada at 32 weeks gestation by menstrual
history. The weight was obtained on a grocery store scale on second day of life
and subsequently was verbally reported to the physician. On follow-up at one
year the child was reported to be healthy and normal physically and mentally.
She was small for her age.
Case No. 6
An 879-gram, 21 week gestation.
Case No. 7
A 999-gram, 22 week gestation.
These two cases were included as survivors in a report by Alden et al.,
Pediatrics 50:40, 1972. When the gestational ages of these infants were re-
evaluated, it was noted that the gestational ages listed were taken from the
obstetrical records of the referring hospital and were probably inaccurate. The
birth weights do not correlate with the aforementioned gestational ages. Accord-
ing to intrauterine growth charts these infants were about 26 weeks and 25-1/2 to
27 weeks, respectively (using the 50th percentiles).
Case No. 8
A 450-gram infant was born in a rural hospital in Poland at 25 weeks gestation
(by last menstrual period) after threatened first trimester miscarriage. Length:
27 cm. Grandmother and granduncle were reported to have been 900 and 1300 gram
prematures, respectively. There is no indication of how these weights were
obtained in 1900-1920. History of three sets of paternal twins. Physical exami-
nation was consistent with last menstrual period gestational age. Child was
normal at three months. The report proposed that genetic factors in this family
might be responsible for increased incidence of very small surviving premature
infants. However, the reported weight, length and gestational age are so incom-
patible as to raise some question as to the accuracy of the facts.
G. Quality of Survival. The impact of the advances in care of premature
infants over the past decade also have been reflected in an improvement in prog-
nosis of very low birth-weight infants. The outlook for these infants born in
the 1950s and 1960s revealed a uniformly poor prognosis for survivors who
weighed less than 1500 grams at birth with handicap rates ranging from 33 percent
to 60 percent. In general, the smaller the infant, the worse the outlook. The
recent study by Stewart and Reynolds (see reference 189) evaluating infants
weighing 1500 grams or less at birth and cared for in their intensive care unit
from 1965 to 1970 is representative of the improved prognosis and survival that
have occurred. Of these children, 90.5 percent had no detectable handicap, while
4.2 percent (4) had mental handicaps and 5.3 percent motor handicaps. An analysis
of the individual children revealed "a clear relationship between the presence
of a handicap and the occurrence of neonatal illness, particularly those presumed
to have caused severe hypoxia." Many of the changes in care in Stewart and
Reynolds' premature unit were directed primarily at decreasing the incidence of
hypoxia. The constellation of these advances which were associated with this
improved prognosis included the use of maternal hormone assays (estriol) and
ultrasonic biparietal diameter measurements to determine a more optimal time for
delivery; continuous electronic fetal heart rate monitoring and fetal acid-base
monitoring to decrease the incidence and severity of intrauterine asphyxia;
improved resuscitation at birth, oxygen therapy closely adjusted to blood measure-
ments; electronic monitoring of respiratory rate in the management of apneic
infants; improvements in artificial and assisted ventilation.
Several examples of specific advances taken from other centers are illus-
trative of the nature of the kind of improvements that have occurred for certain
subsets of patients that result in improved prognosis. At Babies Hospital,
Columbia-Presbyterian Medical Center, long-term follow-up of the low birth-weight
premature infants with Apgar scores of 3 or less at 5 minutes, in association with
intrauterine asphyxia, revealed an incidence of handicap approaching 80 percent.
12-11
Figure 12 depicts a changing morbidity rate as assessed by the Apgar score
at 1 and 5 minutes over three time periods at Babies Hospital. The first is
prior to continuous intrauterine monitoring of fetal heart rate and intermittent
fetal blood acid-base monitoring. The second is during 13 percent acid-base and
25 percent heart-rate monitoring. The third is during 25 percent acid-base and
52 percent heart-rate monitoring. The number of patients included in the first
period is small. They were the only infants at that time who were scored at 1
and 5 minutes and were part of a large group of 37,000 patients from 12 centers
in a collaborative project. Nearly 25 percent of these infants had a 1-minute
Apgar score of 5 or less. This particular incidence of depressed infants at
1 minute was similar for the 37,000 infants of the combined data obtained from
the national collaborative project and appeared for many years to be an irreduc-
ible number, considered a standard figure both in the United States and Great
Britain. With the increasing use of intrauterine monitoring of high-risk patients
and those that showed evidence of fetal difficulty during labor in period two,
the number of depressed infants at 1 minute fell to 13.1 percent and at 5 minutes
to 3.3 percent. This decrease in morbidity in 1972 was associated with 13 per-
cent acid-base monitoring and 25 percent heart-rate monitoring. This lower niim-
ber of depressed infants persisted into the third period when acid-base monitor-
ing increased to 25 percent and heart rate monitoring to 52 percent. For the
niffliber of patients considered, the reduction in the number of depressed infants
at 1 and 5 minutes both from the first to the second and from the first to the
third period is substantial.
When morbidity is measured in terms of duration of hospitalization, a
similar improvement is documented. Figure 13 indicates the duration of stay in
the newborn intensive care unit for 398 infants; 213 were monitored during labor,
while 181 were not. Although the number of monitored patients admitted to the
unit was greater than those who were not monitored, the proportion of monitored
infants requiring extended recovery periods was markedly less than for unmonitored
infants for all admissions of 1000 grams or more. When only those infants weigh-
ing 2500 grams or more were considered, the difference became even more striking.
Figure 14 illustrates that the mean duration for the monitored infants was six
days and for the unmonitored infants ten days. Only 20 percent of the monitored
patients required nine days or more of hospitalization as compared to 40 percent
in the unmonitored group.
Another specific example of decreased morbidity relates to infants with
respiratory distress syndrome or hyaline membrane disease. When the changes in
mortality and morbidity are analyzed in terms of the major cause of neonatal and
premature infant death, respiratory disease, the central importance of advances
in respiratory care designed to improve oxygenation is recognized, e.g., improved
mechanical ventilation and technology to increase end expiratory pressure during
breathing. Despite a constant incidence of respiratory distress syndrome
(Figure 15) , survival has markedly increased (Figures 15 and 16) , as has the
intelligence quotients of survivors at the University of California at San
Francisco.
The possibility that measures taken to increase survival of infants of very
low birth weight would result in increased number of handicapped children entering
the community where they would become a burden on their families and society has
not, in fact, occurred. Rather, these measures taken to increase survival rates
of premature infants have improved the outlook for such surviving infants enter-
ing the community without handicaps. The number of very low birth-weight infants
surviving with handicaps has markedly decreased compared to the period prior to
the institution of the clusters of medical advances that characterize present
neonatal intensive care centers. This is of even greater importance since the
data from the New York City Premature Centers indicate a marked increase in sur-
vival of the 750-1000 gram nonwhite inborn infants in 1973 (Tables 11 and 13) .
3. CHANGES IN MEDICAL TECHNOLOGY AND CARE OF THE PAST DECADE
A. Introduction . Advances in clinical care of human fetuses and premature
infants, as in many other areas of medicine, have not evolved smoothly in a logi-
cal progression of closely related studies with the results promptly accepted
and uniformly applied. In contrast, advances have developed haltingly by a com-
bination of serendipity, empiricism and investigation of a broad spectrum of
interrelated but tangential questions. In no instance has it been possible to
directly translate the results of a fetal animal experiment to human therapy.
Rather, animal studies have occasionally contributed to the background of under-
standing upon which human investigation is, in part, based. Alternatively, only
a few major changes in medical treatment of the premature infant have been the
direct result of carefully controlled human experiments designed to test specific
innovations prospectively. Many have resulted from a combination of suggestive
evidence from basic and clinical experiments, scattered uncontrolled observations
on patients, and inferences from improved understanding of normal physiologic
mechanisms. Continuous fetal heart rate and uterine pressure monitoring to
detect fetal distress and the advances in the diagnosis and treatment of fetal
erythroblastosis resulted from a variety of empiric clinical observations and
poorly or partially controlled studies in normal and affected human subjects.
Animal studies did not contribute to the advances in these instances. The evo-
lution and acceptance of these new modes of treatment were dependent on amassing
cumulative experience and observations over a number of years. In contrast,
defining the optimal temperature for premature infants that would increase sur-
vival resulted in large measure from a combination of carefully controlled
rigorous animal and human experiments. Thus, advances seem eventually to emerge
from a highly diversified matrix of thought and activity of widely scattered
individual scientists and physicians.
B. Sources. These data were obtained from a survey of the English
literature and from the recorded experience and recollections of the consultants
and their associates (physicians, nurses and administrators) involved in providing
medical care in their respective neonatal intensive care centers (NICC) .
C. Limitations. Regular diaries are rarely kept in NICC's to record the
dates when new procedures and therapies are introduced and existing treatments
discontinued. This can be documented by retrospective analysis of patient charts,
but such a study was not undertaken because of time constraints. However, in
selected instances patient charts were checked to evaluate the time periods.
Each consultant was mailed a form on which he or she was asked to indicate
the year when the particular innovations listed were introduced in the center
(see Appendix C) . No attempt was made to survey innovations which were discarded
before or during this period because new knowledge and experience from human
investigation indicated that they were not beneficial or harmful. The consul-
tants filled out the questionnaires individually often after consultation with
other associates in their center. A meeting was then held to clarify questions
about the form and the replies and to determine whether a consensus existed
concerning when the innovations were introduced and when they became disseminated
on a regional or national basis. The consultants also identified critical or
index advances that in their judgment, based on patient care experience, were
most important. These are given special emphasis in this analysis.
The foregoing activity was carried out independently of the analysis of
survival trends presented in this report. Each consultant, however, brought to
these discussions his own perceptions of local and national survival trends.
No attempt was made as a group to relate these discussions to survival data.
This correlation was done later by the authors of this report after the survival
data were obtained from diverse sources and analyzed.
D. Overview. Figure 17 describes in semiquantitative terms the trend in
the numbers of major advances in obstetric and pediatric care of the fetus and
premature infant introduced during each of the past ten years. Particular inno-
vations or constellations are far more important in themselves than is the cumu-
lative frequency of the number of innovations when trying to assess the impact on
mortality and morbidity. Further, in general it takes one to three years from the
introduction of an innovation at one or several centers to its acceptance in most
centers around the country and Canada, and in some instances, in community hospi-
tals. Further, many advances are of such a technical or specialized nature that
they are only appropriately used in neonatal intensive care centers where risks
can be kept at an acceptable level relative to benefits and where, generally,
there is continuous, critical, open and objective evaluation of patient mortality
and morbidity.
The improvements in overall survival rates of prematures noted on page 12-4
in 1967-1969 may be related to the advances in 1964-1966. These advances con-
sisted of a constellation of changes that included reorganization of premature
nurseries into intensive care centers with extensive monitoring of blood gases,
and chemistries; continuous physiologic monitoring of vital signs; emphasis on
hand ventilation with ambu bags; regulation of the thermal environment; a greater
density of nursing personnel; and a more aggressive approach to correction of
abnormal laboratory values, e.g., hypoxia, hypoglycemia. In 1962-1966 there was
also a major obstetrical advance with the in utero diagnosis with amniocentesis
of severely affected fetuses with erythroblastosis and the introduction of intra-
uterine fetal peritoneal transfusion.
In England a similar conclusion to that from the United States data was
drawn from the mortality trends at University College Hospital and Medical School,
London. Only 45 to 50 percent of infants weighing 1001 to 1500 grams survived in
the 1950s and early 1960s. In contrast the survival rate for inborn and out-
born averaged 69 percent and 70 percent respectively, during 1966-1970 when the
12-14
aforementioned cluster of neonatal intensive care advances was introduced in
their premature unit. The lag between introduction of these changes and improve-
ment in morbidity is greater than the lag between introduction and survival
because the children need to reach preschool and school age before adequate
assessment can be obtained. It is now becoming apparent that there has been an
improvement in morbidity probably related to these innovations in the mid-1960s
(see page 12-14) . , • , .
The increases in survival in 1971-1973 may reasonably be correlated with a
different constellation of advances in 1958-1970: extensive monitoring of the
amniotic fluid for chemical abnormalities, inborn errors of metabolism and the
diagnosis of fetal lung immaturity; increased use of maternal estriol determina-
tion in managing high-risk pregnancies; the introduction of continuous fetal
heart rate and uterine pressure monitoring with ultrasound to detect and aggres-
sively manage fetal asphyxia during labor; the use of neonatal transport systems
and improvement in physiologic support during referral; major advances in the
design and use of infant respirators and the management of respiratory distress
syndrome with various techniques to provide increased end expiratory pressure;
the use of total intravenous alimentation in premature infants; and the extensive
use of phototherapy for jaundice.
E . Major Changes in the Technology and Care of Premature Infants.
Appendix C contains a detailed listing of the innovations in care of premature
infants that have been assimilated into the routine practice of premature
intensive care. Several of these have been selected for further discussion in
order to assist in clarifying the meaning of some of the medical terminology and
"jargon" which have been used to describe the advances of the past decade.
(1) Determining Gestational Age of the Newborn Infant After Delivery.
The gestational age of the newborn infant at birth is important in predicting
the mortality rate and the best way of handling infants of certain weights and
ages. During the past decade it has been increasingly appreciated that different
clinical problems develop in newborns of the same weight but different gestational
ages and, therefore, they require different plans of therapy. Studies of these
variations in expected weight for gestational age have been increasingly used to
improve care. For example, preterm infants who are small for gestational age
have a lower mortality rate than preterm newborns of appropriate gestational age,
while term infants of low birth weight have a higher mortality rate than term
infants of normal birth weights.
There are several ways of determining the gestational age of the newborn
infant. These include: (1) physical examination; (2) neurological examination;
(3) nerve conduction time; and (4) electroencephalogram. The most accurate
estimate of gestational age is obtained by using a combination of several of the
above methods. In order to evaluate gestational age by physical examination,
the extent of sole creases, breast nodule diameter, quality of scalp hair,
cartilage of the ear lobes, descent of testes, and rugation of the scrotum are
evaluated (see Figure 18) . The neurological evaluation is usually done at
48 hours of life. This is a difficult examination, especially in the small pre-
mature infant. Also, one has to be careful of its interpretation in a sick new-
born infant. Figure 19 illustrates the neurological findings that are used to
diagnose the neurological maturation and thereby the gestational age of the
infant. A third method, which is the most accurate {+2 weeks) method used, to
determine gestational age is the motor nerve conduction velocity which is
dependent on the degree of myelination of the peripheral nerve fibers. This
increases with age during the gestational period. For example, low birth weight
and small- for-dates infants have higher nerve-conduction velocities than pre-
term infants who are of the same weight but are of appropriate gestational age.
The conduction velocities are measured by stimulating the ulnar nerve at the
elbow and the wrist with rectangular supramaximal stimuli at two different points
and recording the evoked muscle action potential (Shulte) . The electroencephalo-
gram (EEG) is another method of measuring gestational age. The EEG reflects the
degree of maturation of synaptic structures in the central nervous system. By
analyzing the pattern of the EEG one can also estimate the gestational age of
the infant within j^2-3 weeks. It is only practical to carry out the general
clinical and neurological estimation of gestational age in the delivery room.
(2) Resuscitation. Resuscitation in the delivery room has been per-
formed with increasing effectiveness and innovation in recent years. Resusci-
tation refers to a group of techniques and procedures, the cornerstones of which
are artificial ventilation with mask, or endotracheal or nasotracheal tube, and
external cardiac massage. In addition to evaluating and supporting the newborn's
cardiac and respiratory systems, it is important to maintain body temperature in
premature and asphyxiated infants who are very sensitive to cooling. Newborn
beds in the delivery room may have radiant heaters for this purpose, with servo-
controls to automatically adjust the heat provided to the heat lost from the
skin.
For any infant who has passed meconium during labor or has meconium-stained
amniotic fluid, the posterior pharynx and larynx are examined. If any mecomiun
is seen in this area, it is suctioned under direct vision and the larynx is
intubated and suctioned by mouth to tube suction until watery mucus is obtained.
This is done to prevent meconium aspiration, which results in a high morbidity
and mortality in the newborn. Meconium is passed per rectum by the fetus
following an asphyxial (poor oxygenation of the fetus) episode in utero. If
this asphyxia is severe enough, it may be accompanied by prolonged gasping. At
this time, the fetus may aspirate meconium into his lungs.
Another technique that may be used in the delivery room is measurement of
the acid-base status of the newborn. This is important in determining his
respiratory and metabolic state at birth. This can be done easily by double-
clamping the umbilical cord and obtaining blood from the umbilical vein and
artery for acid-base analysis. This is especially important in low birth-weight
and asphyxiated infants.
An additional development over the past decade has been the administration
of buffers like sodium bicarbonate through the umbilical vein or a peripheral
vein to correct acidosis (low pH) due to in utero asphyxial episodes which
require resuscitation. During prolonged asphyxia there is depression of the
central nervous and cardiovascular systems and biochemical changes which result
in acidosis in the fetus. Acidosis further potentiates this depression. Asphyxia
may be associated with maternal factors like hypotension, toxemia of pregnancy,
inferior vena cava obstruction by a large uterus; and fetal factors such as
umbilical cord occlusion. Infusion of buffers (correcting the acidosis) and
glucose during artificial ventilation of these infants may speed their responses
to resuscitation.
(3) Catheterization of Umbilical Vessels in the Newborn Infant. The
umbilical artery and vein are located in the umbilical cord and, in utero, carry
blood between the fetus and placenta. Under appropriate circumstances (outlined
below) either vessel may be cannulated with an inert, soft, radiopaque plastic
catheter after birth.
For umbilical artery procedures the catheter is passed through the artery
to a location about 1 cm above the diaphragm or between the iliac bifurcation
and the renal arteries. Catheter location is verified by X-ray. The catheter
is Jcept open with a slow infusion. This procedure is indicated for the newborn
or premature infant who requires oxygen therapy either unassisted or with a
respirator. Arterial blood samples are drawn from the catheter as indicated
clinically to determine the degree of oxygenation of the blood (which in turn
reflects the respiratory status of the patient) . The importance of doing this
is to prevent retrolental fibroplasia and other forms of oxygen toxicity. The
arterial catheter also can be used to measure the intra-arterial blood pressure
via a transducer. This is continually projected on an oscilloscope monitor and,
if needed, is connected to an alarm system.
Umbilical vein catheterization may be done (1) as an emergency procedure
in the delivery room to administer fluids like glucose water or buffers such as
sodium bicarbonate to correct early acidosis (see Resuscitation) , (2) for intra-
venous feeding of very small prematures when it is impossible to maintain a
peripheral intravenous line, and (3) for exchange transfusions for hyperbilirubi-
nemia (jaundice) .
(4) Electronic Monitoring of the Neonatal Infant. The development of
several kinds of monitors in recent years has improved the care of the high-risk
and sick infant.
Apnea monitors are of two kinds. The first type runs on the principle of
impedance plethysmography utilizing electrodes which are applied to the child's
chest and/or arms. The monitor is set at a certain regulatory rate and time
(15-20 seconds) . When the infant has an apneic episode (stops breathing for
longer than 20 seconds), an alarm goes off to alert the personnel. Another type
is an air-filled mattress with a temperature sensing device that detects movement
of air coincidental with respiration. When apneic episodes occur, an alarm
sounds .
Cardiac monitors record the heart rate of the newborn using electrodes
strategically placed on the infant's chest and extremities. The heart rate is
recorded either on an established scale or displayed on an oscilloscope as the
electrocardiographic figure. The monitor is set at a certain rate and when the
heart rate falls below this, an alarm goes off.
12-17
Blood pressure is measured in the neonate by several methods , but the most
accurate and most commonly used in the neonatal intensive care units are the
intra-arterial and Doppler methods. Intra-arterial blood pressure is measured
via the umbilical arterial catheter, as described previously, via a transducer
and is projected on an oscilloscope as the number or wave form. The transcu-
taneous Doppler method is a noninvasive method and detects very weak impulses
which a regular sphygnomanometer would not detect. Studies have established a
good correlation between the Doppler and arterial blood pressure.
Temperature. Appropriate temperature control is of utmost importance to
the premature low birth-weight infant. The survival of prematures can be
improved by proper heat control. If the artificial environment is too warm,
the newborn becomes febrile and tachypneic. If it is too cool, the energy and
oxygen requirements will increase to generate more heat, decreasing the energy
stores which are already low in prematures, causing metabolic acidosis and
hypoglycemia. Cold may interfere with surfactant production in the lung
(increasing likelihood of respiratory distress syndrome). Thus, it is important
to keep the infant, especially the low birth-weight infant, in a neutral thermal
environment (temperature of 34. 5-36. 5°C) . In most isolettes used today in the
intensive care units the heat is controlled by using a fan to circulate warm air
and the temperature of the isolette is controlled by the infant's skin temperature
via a cutaneous sensory thermistor connected to the abdomen. New "open beds" with
radiant heat units above the bed are used in some intensive care units and
delivery room as treatment beds instead of isolettes. These are also controlled
by thermistor probes taped to the infant's abdomen.
Microchemistry . The development of rapid microchemistry techniques for
analyzing the chemical abnormalities in the newborn has greatly helped the care
of these high-risk sick infants. Because of the small amount of blood needed,
it is now possible to monitor many chemical parameters as, for example, blood
glucose, calcium, electrolytes, bilirubin, liver chemistries, Mg, P, etc. Chemi-
cal aberrations can be corrected much sooner and injury prevented. New micro-
techniques have also been developed for hematological tests (blood typing and
counts, G6PD, vitamin E levels, etc.).
Blood gas analyzers that only require a very small amount of blood and are
easy to operate have greatly improved the respiratory care of newborn infants.
This machine is often located within the intensive care area and operated by the
physicians involved in the infant's care. This provides immediate results on
the respiratory status of the infant so appropriate changes in therapy can be
made.
(5) Oxygen. Oxygen can be delivered into the isolette when small
increases in the environmental oxygen are needed or into a plastic head box within
the isolette when higher concentrations of oxygen are needed. Using the head box,
more accurate concentrations of oxygen can be delivered and fluctuations in oxygen
concentration can be prevented. The oxygen delivered must be warmed and humidified.
If the oxygen is not warmed, it may be a cold stress to the sick premature and if
it is not humidified, it will dry the respiratory mucus, increasing the viscosity
of the pulmonary secretions, worsening the newborn's respiratory distress. Monitors
are now available for continual oxygen monitoring in the isolette or headbox. A
12-18
monitor is set at the desired oxygen concentration and, if the environmental
oxygen is at a too high or too low point, an alarm goes off. The setting is,
of course, determined by the infant's respiratory condition (arterial and capil-
lary blood gases) .
(6) Mechanical Ventilation. The criteria for mechanical ventilation
(respirator therapy) vary from one intensive care unit to another. Each inten-
sive care unit has its own criteria for when to place an infant in respiratory
distress on the respirator, but one common indicator is apnea (no breathing).
At present, either an orotracheal or nasotracheal tube is used for artificial
ventilation. Tracheostomies are occasionally used for long-term ventilation.
There are many types of positive and negative pressure respirators available.
Positive pressure respirators are either pressure or volume controlled. The
method of ventilation depends on the individual unit. Regardless of the type
of respirator, the infant must be followed with repeated blood gases to deter-
mine its efficiency and infant's progress.
Recently, continuous positive (CPAP) and negative airway pressure and
positive end expiratory pressure (PEEP) have been introduced for the treatment
of respiratory distress syndrome. The principle of this is to not allow the
diseased lungs to collapse at the end of expiration but to keep the alveoli open
by a continuous distending pressure and thereby improve the diffusion of gases
(oxygen and carbon dioxide) . Infants who have RDS often grunt. The grunt is
produced by exhaling against a partially closed glottis which increases the
transpulmonary pressure. This probably prevents and decreases the extent of
collapse of the alveoli (air sacs of lungs) . In respiratory distress syndrome
a large percent of the alveoli are collapsed at the end of expiration due to
the lack of surface active material (surfactant) which is necessary to prevent
their collapse. The use of constant distending pressure functioning in principle
like a grunt has decreased the mortality rate of respiratory distress syndrome.
CPAP can be delivered via a head box, mask, nasal prongs or endotracheal tube.
If mechanical ventilation is necessary, the positive pressure (PEEP) is delivered
via the endotracheal tube at end of expiration. All of the above methods require
an expert staff of dedicated and skilled physicians, nurses and respiratory
technicians .
(7) Nutrition. Feeding practices have changed in the last decade. In
the 1950s and early 1950s full-term infants were not fed for the first 12-24 hours
and premature infants were not fed before 24-36 hours of life. It is now known
that early feeding of infants is important in decreasing morbidity and mortality.
As soon as an infant can tolerate feedings, they are started, usually between 4-6
hours of age and earlier in small-for-dates infants or infants of diabetic mothers.
This may decrease the incidence of hypoglycemia, hyperkalemia (high potassium),
hyperbilirubinemia and azotemia. Very low birth-weight infants are still a
special problem because of their inability to suck, small stomach capacity and
danger of aspiration. These infants are usually fed by gavage (tube passed into
the stomach at feeding times — every 2-3 hours) and supplemented with glucose
water intravenously for adequate fluid intake and supplemental calories.
12-19
An alternative method is nasojejunal feedings in which a tube is passed
into the jejunum (small intestine) . This method decreases the chance of aspira-
tion, provides greater volume of formula than is tolerated by the stomach, and
can be used in sick teirm and premature infants.
Another recent development is total intravenous alimentation. It may be
used when enteral nutrition is not possible for prolonged periods in infants of
very low birth weight and after radical gastrointestinal surgery. This provides
continuous infusion of fluid, calories, electrolytes and vitamins. The solution
consists of amino acids, hypertonic glucose, electrolytes, and vitamins. It can
be infused either via a peripheral vein as a supplement to oral feedings or via
the internal or external jugular vein for a prolonged time as a total source of
nutrition. There are serious risks associated with this treatment. It should
only be used with very experienced personnel and in the presence of an adequate
microchemistry laboratory.
(8) The Neonatal Intensive Care Unit. This unit admits any infant
under six weeks of age who requires intensive care, including premature infants.
This includes any sick infant with infection or respiratory distress, any infant
requiring major surgery or special nursing care (e.g., infants needing hyper-
alimentation or tracheostomies and infants of birth weight less than 1500 grams) .
The nursing personnel undergo special training and orientation in order to work
in these units and are provided ongoing education covering new techniques and
instruments used in the intensive care unit. There is usually a 1:2 nurse to
patient ratio and 1:1 ratio for the sickest infants. The physicians include
a full-time doctor trained in neonatology, full-time pediatric housestaff,
including neonatal fellows, a full-time anesthesiologist and consultants in a
variety of specialties. It is in such units that most of the medical advances
relevant to newborn infants have been initiated over the past decade.
(9) Transportation and Regionalization of Care. In recent years
premature transport systems, using ambulance and/or helicopter, have been estab-
lished in many rural and urban areas in the United States. The purpose of such
a system is to bring high-risk infants from hospitals not equipped to care for
such newborns to units where they will obtain proper care. Specially trained
personnel are necessary for this transport. Some transport ambulances are
equipped as small intensive care units, and carry respirators and laboratory
equipment in order to provide immediate care for the critically ill newborn
before starting the transfer to a special care unit. Thus, the constellation of
advances that make up intensive care have been applied outside of the hospital.
Regionalization of care includes the transport of sick newborns to a spe-
cial care unit from several participating hospitals in the area which are not
capable of providing intensive care. Regionalization also includes the education
of physicians, nurses and ancillary staff in recognizing the sick newborn and
being able to care for some of the less ill neonates.
(10) Transitional Care Nurseries. The transitional nursery is usually
located close to the labor-delivery suite. Infants born to high-risk mothers
(toxemia, diabetes, drug addiction, fever, Caesarian section, Rh sensitization.
cardiovascular disease, etc.), infants of low birth weight (either preterm or
small-for-date) and distressed infants (respiratory, shock, asphyxia) are admitted
to this unit for stabilization and observation for no longer than 5-8 hours before
transfer to the regular nursery or the intensive care unit. The transitional
nursery is supplied with the necessary equipment to sustain the sick newborn,
including monitors for heart rate, respiratory rate, temperature and other emer-
gency equipment. The staff includes a specially trained pediatrician, registered
nurses and aides. Laboratory and x-ray facilities are also available for this
unit.
(11) Phototherapy. Phototherapy is a new mode of therapy used to
treat hyperbilirubinemia. It is especially applicable to sick or premature
neonatal infants who are much more susceptible to bilirubin encephalopathy at
lower levels of bilirubin than healthy full-term infants. In addition, hypoxia,
acidosis and cold stress may increase this susceptibility as well as immaturity
of the liver in metabolizing bilirubin. Phototherapy is also used in ABO
incompatibility and postexchange for Rh incompatibility and appears to have
decreased the number of exchange transfusions that may be required to lower serum
bilirubin levels. The exposure to light of high intensity decreases the level
of serum bilirubin. It is thought that the bilirubin is decreased by photo-
oxidation which take's place mainly in the peripheral tissues. It may also pro-
mote hepatic excretion of unconjugated bilirubin. A decline of 1-4 mg percent of
seriom bilirubin can be expected in nonhemolytic jaundice after 8-12 hours of
exposure. However, the potential long-term effects of exposing a substantial
segment of our newborn population to this new mode of treatment has not been
evaluated.
(12) Fetal Electronic Monitoring. Fetal heart rate monitoring,
including the analysis of beat-to-beat variation and its relationship to uterine
contraction has become a very significant means of decreasing perinatal morbidity
and mortality. It provides predictive information about the condition of the
fetus during labor and influences the obstetrical management. The fetal monitor
receives an electrical signal from the fetal heart by several different methods:
from a microphone strapped to the maternal abdomen, from abdominal electrocardio-
graphic electrodes, from an electrode applied transcervically to the presenting
part, or from transabdominal ultrasound sensor. The fetal heart rate pattern
is correlated with the uterine contractions recorded either directly by intra-
amniotic catheter or indirectly by an abdominal tocodynamometer . The following
are evaluated: (1) Beat-to-beat variability in heart rate. The normal fetal
heart rate shows variability or irregularity that reflects central nervous system
control. A decrease in variability may reflect the effect of a drug as, for
example, atropine, barbiturates, tranquilizers, or narcotics which were given to
the mother in labor. (2) The heart rate. There are three types of decelerations
(decrease in heart rate) that may occur during labor: (a) early deceleration
begins with the uterine contraction and returns to the baseline heart rate at the
end of contraction. This is interpreted to be due to fetal head compression. The
head compression results in a cardiac slowing which is probably mediated via the
vagus nerve. It is not associated with an increase in fetal morbidity or mortality.
(b) Late deceleration occurs after the beginning of contraction and ends after the
contraction. This is thought to be due to utero-placental insufficiency resulting
12-21
in anoxia of the fetus. These patterns are often associated with changes in the
acid-base status of the fetus and may result in neonatal depression. (c) Vari-
able deceleration is slowing of the heart rate with no relationship to the onset
of contractions. It is highly irregular and may be abrupt. This type of decel-
eration is thought to be due to intermittent compression of the umbilical cord
between fetal parts and the contracting uterus . It may be mediated by the vagus
nerve. If the deceleration is prolonged or associated with a decrease in beat-
to-beat variability, it can lead to anoxia. This is usually of short duration,
benign and is often eliminated by change in the maternal position.
Another tool for examining the well-being of the fetus is the determination
of the pre-ejection period of the cardiac cycle which represents the time from
the onset of QRS complex to onset of ejection from the left ventricle. This can
be measured from the ECG and Doppler ultrasound. It is related to the myocardial
contractility and therefore is helpful in assessing the state of oxygenation of
the fetal myocardium.
A new experimental method in fetal monitoring is the measuring of fetal
respiration by recording fetal chest movements by ultrasound. Fetal chest move-
ments occur at a frequency of 40-70/minute and are normally present for about
70 percent of the time during the last half of the gestation. Hypoxia and hypo-
glycemia are associated with a decrease in respiratory movements in the fetus
and therefore this may be another sensitive method to detect fetal distress
in utero.
(13) Fetal Stress Tests. Contraction stress test or oxytocin chal-
lenge test is a measure of the fetal welfare and placental reserve before the
onset of labor. It is done by monitoring the fetal heart rate changes by exter-
nal monitors, either microphone or ultrasound transducers, for 30 minutes under
simulated labor, either induced by pitocin stimulation or spontaneous contrac-
tions. A negative test shows a stable heart rate and, if indicated, may be
repeated every seven days in high-risk pregnancies. A positive test shows
repeated late decelerations and is associated with poor fetal well-being and
tolerance of labor.
(14) Erythroblastosis Fetalis or Rh Incompatibility. The prognosis
of erythroblastosis fetalis has changed greatly in the last ten years as a result
of the introduction of amniocentesis and evaluation of the bilirubinoid pigment
in amniotic fluid by spectrophotometry, intrauterine transfusions, early induc-
tion of labor, exchange transfusions and aggressive intensive care of the newborn
(mainly respiratory) and most recently the development of a method to prevent the
disease. About 20 percent of fetuses were stillborn and 30 percent died in the
neonatal period or were brain damaged. Now the perinatal mortality in those
infants in whom the disease is not prevented has been reduced to about 5-10 per-
cent.
An antibody titer is performed on each Rh negative mother during pregnancy
(serially in the first sensitizing pregnancy) and if the titer is greater than
1:16, an amniocentesis (removal of fluid from the "bag of waters" surrounding
the fetus) is done to analyze for bilirubin pigment in the amniotic fluid. This
bilirubin pigment has been identified as unconjugated bilirubin bound to albumin
by spectral analysis. The spectral absorption of amniotic fluid is plotted on
a semilogarithmic scale. In a normal pregnancy it was determined to be a straight
line. If bilirubin is present there is a deviation at a specific wavelength
(450 mu) . The concentration of bilirubin is derived from the difference between
the normal spectral curve and the spectral curve of the patient's amniotic fluid
at this wavelength (A OD 450) . On the basis of several hundred pregnancies,
values have been derived that correlate with the extent of sensitization. The
initial amniocentesis in a first pregnancy is usually done at about 28-29 weeks
gestation. In previously severely sensitized pregnancies it is done at 22-23
weeks gestation and repeated at 1-3 weekly intervals. Based on these results
patients may be delivered spontaneously (where the risks of prematurity are less
than the risks of the disease or other treatments) or patients may receive intra-
uterine transfusions. Intrauterine transfusions are performed by slowly inject-
ing packed red cells compatible with the mother's blood into the fetal peritoneal
cavity from where they are absorbed via the diaphragmatic lymphatics. Prior to
the procedure, radio-opaque water soluble dye may be injected into the amniotic
cavity to identify a hydropic fetus and to localize the placenta and the gastro-
intestinal tract on X-ray and fluoroscopy as a guide for proper needle placement.
Intrauterine transfusion may be repeated every ten days until delivery. In
recent years a method has been devised to prevent the disease in a fetus by
preventing formation of the maternal antibody. This is done by destroying fetal
cells which sensitize a mother to produce antibodies when they cross into her
circulation.
(15) Assessment of Fetal Lung Maturity. The lecithin/sphingomyelin
ratio (L/S) is a measure of the relative proportion of two phospholipids manu-
factured in the lung of the fetus which may be detected in the amniotic fluid.
Maturity of the fetal lung occurs at about 35-36 weeks gestational age and is
demonstrated by a sudden increase in the lecithin fraction. When evaluation
of lung maturity is desired in order to decide when to do Caesarian section
or when to deliver an infant early for Rh incompatibility or maternal diabetes,
an amniocentesis is done. The fluid is analyzed for the lecithin/sphingomyelin
ratio by thin-layer chromatography. The concentration of lecithin is low and
less than sphingomyelin until about 30-32 weeks of gestation when they become
equal. Subsequently the lecithin concentration increases and sphingomyelin
decreases. A mature L/S ratio is about 2 (depending on the laboratory).
Lecithin is part of the surface active material necessary to lower the surface
tension of the alveoli in the lung and prevent their collapse. The L/S ratio
and lecithin and its precursors can be measured postnatally in tracheal fluid.
If L/S ratio or lecithin or its precursors remain low when measured serially,
the prognosis is very poor for the newborn regarding recovery from respiratory
distress syndrome.
(16) Urinary Estriol. Maternal urinary estriol is a measure used
to evaluate the well-being of the fetus. This reflects the intactness of the
fetoplacental unit. For this purpose the metabolism of estriol cannot be
adequately studied in any animal. The human fetal adrenal gland synthesizes
dehydroepiandrosterone (DHA) . This is then hydroxylated by the fetal liver
and then converted into estriol by the placenta and fetal liver. Most of the
estriol measured in the maternal urine (90 percent) is derived from the fetal
DHA. The daily estriol excretion rises as normal gestation progresses and at
term reaches values of 10-40 mg/24 hours in maternal urine. The measurements
of estriol have to be done serially in the management of high-risk pregnancies.
If consistently falling values are found (down to 2 mg/24 hours of maternal
urine) , this may indicate impending fetal death. There are other reasons for
low estriol levels as for example small-for-gestational-age fetus, fetal hypo-
adrenalism, ampicillin, phenobarbital. These do not require immediate inter-
vention. Thus, in evaluating the fetus and deciding upon the management of
pregnancy, estriol alone is not relied upon.
(17) Betamethasone . Betamethasone, a glucocorticoid, if given to
mothers in premature labor at gestational age of 28-32 weeks, may prevent the
neonatal respiratory distress syndrome or hyaline membrane disease. It has
been suggested that the betamethasone, given 24 hours prior to delivery, causes
premature liberation of surfactant which is necessary to keep the alveoli of
the lungs from collapsing. Betamethasone is thought to do this by inducing the
enzyme concerned with synthesis and release of stored surfactant. In Dr. Liggin's
uncontrolled series of pregnant women there was a drop from 25.8 percent to
9 percent in the development of respiratory distress syndrome in their infants
and there were no deaths in this group of infants from respiratory distress
syndrome. There may, however, be untoward effects in infants born to women
who have toxemia. As stated, the betamethasone has to be given in two doses
24 hours prior to delivery in order to affect lung function. Because it is
necessary to delay labor in these women for the desired effect, drugs such as
alcohol (10 percent solution) and magnesium sulfate (1-2 gm/hour) have been used
intravenously with success in a limited number of patients in order to allow
time for the betamethasone to work. These drugs require further study in the
fetus. More recently, adrenergic agonists such as orciprenaline and ritodrine
have been used to inhibit uterine contractions experimentally in this country.
These drugs seem to be more effective in stopping labor and may have very
minimal effects on the fetus (slight increase in fetal heart rate) .
F. Potential Areas for Medical Advances Directly Related to the Care of
Premature Infants Which May be Dependent in Part on Investigation of the Human
Fetus and Premature Infant During the Next Decade. Attempts to predict future
investigative needs are hazardous because of the nature of the way medical
advances evolve (see page 12-13) . No projections will be attempted in regard
to the increasing number of suggested relationships between adult diseases and
early development. However, there are at least four areas where research should
be encouraged now because of the improvement that is likely to result in survival
rates of premature infants and in the health and biologic potential of those
infants who survive. Research on previable fetuses and premature human infants
might play an important role in progress in these areas.
(1) Prevention of Prematurity. This is dependent on research into
the mechanisms that control the maintenance of pregnancy, its termination and
labor. Five lines of investigation are involved: (1) the effects of normal and
abnormal placental hormonal secretion during pregnancy; (2) the regulation of
the onset and progress of labor by new drugs; (3) the use of drugs to accelerate
fetal maturity; (4) the development of new methods to estimate fetal maturity and
weight; and (5) the application of technology to monitor the health of the fetus
before birth more closely and accurately.
(2) Prevention and Treatment of Birth Defects (Inborn Errors of
Metabolism, Genetic Effects and Organ Malformations) . At least two lines of
investigation are emerging: (1) development of new and improved methods of
early diagnosis; (2) research into regulation of early cell differentiation and
the control of organ development during very early fetal life.
(3) Improved Oxygenation of Premature Infants With Respiratory
Disease. Three lines of research are apparent: (1) investigation directed at
improving the technology of artificial mechanical ventilation and aids to spon-
taneous respiration (increasing efficacy and decreasing risks) ; (2) the develop-
ment of an artificial blood oxygenating system which can be used for prolonged
periods (over weelts) in place of mechanical ventilation with respirators;
(3) the investigation of measures to more closely and continuously monitor tissue
oxygenation.
(4) Evaluation of the Efficacy and Risks of Drugs in the Fetus and
Premature Infant. This involves the study of drugs administered to pregnant
women for appropriate medical indications, drugs approved for adults but not for
fetuses or children that might be of benefit to the fetus or newborn infant; the
evaluation of new pharmacologic agents developed for diseases peculiar to the
fetus and newborn or of high incidence in this period of life; and studies of
agents that may accelerate maturity of the respiratory system.
4. FORMULATION OF GUIDELINES FOR PHYSICIANS
A. Viability and Nonviability . A fetus or prematurely delivered infant
is biologically viable when a minimal number of independently sustained, basic,
integrative physiologic functions are present. In order for the fetus or infant
to be viable the sum of these functions, considered together, must support the
inference that the fetus or premature infant is able to increase in tissue mass
(growth) and increase the number, complexity and coordination of basic physio-
logic functions (development) as a self-sustaining whole organism. This must be
independent of any connection with the mother and when receiving only generally
accepted medical treatments. If, in sum, these coordinated functions are not
present, the fetus or prematurely born infant is biologically nonviable since it
is incapable of being made able to exist as a self-sustaining whole organism
independently of any connection with the mother. This may be the case even
though some signs of life are apparent.
12-25
At this time (March 1975) the following functions taken together constitute
the minimal number of basic integrative physiologic functions:
• The perfusion of tissues with adequate oxygen and the prevention of
the increasing accumulation of carbon dioxide and/or lactic and
other organic acids. This function consists of these components:
Inflation of the lungs with oxygen
Transfer of oxygen across the alveolar membranes into the
circulation and the elimination of carbon dioxide from the
circulation into the expired gas
Cardiac contractions of sufficient strength and regularity to
distribute oxygenated blood to tissues and organs throughout
the body and to eliminate organic acids from those tissues and
organs .
• Neurologic regulation of the components of the cardiorespiratory
perfusion function, of the capacity to ingest nutrients, and of
spontaneous and reflex muscle movements.
The foregoing minimal basic integrative physiologic functions cannot at
present be separately assessed in the fetus or prematurely delivered infant in
a consistent, reliable and exact manner. The absence of the sum of these mini-
mal functions, however, can be assessed indirectly in a reasonable and reliable
manner by measurement of weight and/or an estimation of gestational age, since
specific weights and gestational ages correlate with a lack of potential for
subsequent sustained extrauterine growth and development (survival) . In this
biologic sense, fetuses or prematurely delivered infants of less than 601 grains
and/or of 24 weeks or less gestational age, may be considered nonviable. At
these weights and gestational ages signs of life such as a beating heart, spon-
taneous respiratory movement, pulsation of the umbilical cord and spontaneous
movement of voluntary muscles are not adequate in themselves to be used to
determine the existence of these minimal basic integrative functions, e.g., the
heart may continue to beat for as long as 30 minutes after removal from the body.
In addition, regardless of weight and gestational age, the minimal number
of basic integrative physiologic functions to sustain subsequent extrauterine
growth and development (survival) are not present in fetuses or prematurely
delivered infants with:
1. Severe malformations of the central nervous system, such as
anencephaly
2. Severe grotesque multiple system malformations, such as cyclops
3. Severe fetal asphyxia or anoxia when there has been no response
to manual resuscitation according to the existing medical practice.
In contrast, a weight of 601 grams or more and gestational age of 25 weeks or
more may indicate that the minimal number of basic integrative physiologic
12-26
functions necessary for independent growth and development is present. Such a
fetus or prematurely delivered infant may be considered biologically viable.
At these weights and gestational ages a sign of life such as a beating heart,
spontaneous respiratory movement, pulsations of the umbilical cord or spontaneous
movement of voluntary muscles should be present to confirm that the minimal num-
ber of basic integrative physiologic functions necessary for survival exist.
B. Fetal and Premature Infant Death. Fetal death or the death of a pre-
maturely delivered infant, who has been determined to be viable, is judged to
have occurred when there is a cessation of the minimal basic, independent inte-
grative physiologic functions which, considered together, may result in sustained
extrauterine growth and development or survival. The absence of all of the
following indicates the cessation of these minimal basic independent integrative
physiologic functions :
1. A heart beat
2. Spontaneous respiratory movements
3. Spontaneous movement of voluntary muscles
4. Pulsation 6f the umbilical cord.
When a prematurely delivered infant is being artificially ventilated, the
absence of all of the above physical signs may no longer be reliable as an index
of the cessation of the minimal basic integrative physiologic functions. Under
these circumstances, the presence of two flat electroencephalograms obtained
24 hours apart when the infant is not receiving central nervous system depressants
should also be used to indicate a cessation of the minimal number of basic inte-
grative physiologic functions necessary for independent growth and development
which characterize biologic life for the fetus and prematurely delivered infant.
The technique of obtaining an electroencephalogram is difficult to apply to pre-
mature infants because of the low voltages generated and other technical problems,
the limited sensitivity of the instruments, the nature of the electrical patterns
from the immature cortex and the very small number of premature infants that have
been tested. There are few adequate published reports and these do not provide
precise details about weights and gestational ages in relation to EEG patterns.
Nevertheless, the above EEG test for determining death of an infant on a ventilator
is, in the judgment of all of the consultants, the best that can presently be for-
mulated. The special problems of recording from the fetus in utero and the almost
total lack of experience with preterm fetuses preclude the use of the electroen-
cephalogram to determine the death of a fetus in utero.
C. Options and Their Implications for Premature Infants. Three general
approaches to this problem can be delineated. First, the fetus could be defined
as a person from the moment of conception and the fetal interests or individual
rights allowed to override the interests of all other individuals and society.
Since the fetus would not be physically capable of consenting, there could be no
human fetal research. Second, the fetus could be defined as part of the mother's
body until the moment of birth and the mother's interests or individual rights
allowed to override all other individual rights or interests of the society as
12-27
long as she consented. Fetal research at any stage, thus, would present few
moral problems. Biologic facts could be marshalled for and against both propo-
sitions but could not prove either extreme position.- However, to accept either
extreme or some minor variation of one .of these positions involves some risks
for society. DeTocqueville has cautioned that "Human institutions are so imper-
fect by natxire that in order to destroy them, it is almost always enough to
extend their underlying ideas to the extreme."
The third approach is to use the idea of viability as a mechanism for
achieving an optimum balance between the interests of the several involved indi-
viduals and society. Such a solution should be based on a reasonable interpre-
tation of biologic facts and should minimize the conflicts between the more
important social interests and activities which are at stake.
For the viable fetus or premature infant, as for the adult, human investi-
gation is presently considered unethical by the medical profession unless:
(1) the potential therapeutic benefit for the individual is reasonably judged
to outweigh the risks or if there is no potential therapeutic benefit, then the
potential benefit for society is large and the likely risks to the individual
judged to be small or inconsequential, and (2) the individual or a valid surro-
gate consent after receiving adequate information and explanation. A competent
adult may take considerable personal risks even for no therapeutic benefit in
the, name of a greater social good. In the case of an incompetent adult or a
child for whom a surrogate is designated to make the judgment, a de facto fidu-
ciary relationship exists. When there is a potential therapeutic benefit for
the individual, even though remote, the surrogate, usually a relative, may make
decisions (including decisions which objectively are poor decisions) which can
have untoward consequences for the patient, their family and society. In our
opinion, if a surrogate is permitted to make a decision when there is no poten-
tial therapeutic benefit, the risks should be very small or inconsequential and
the potential benefit to the class, of which the subject is a member, potentially
very large.
There are three major additional interrelated issues involved when con-
sidering the nonviable fetus:
1. The delineation of a weight and/or gestational age below which the
probability of survival is so small as to be judged to be essentially
nonexistant (when weight is used as an index of the presence of ade-
quate independent coordinated functions for a whole organism to
survive)
2. Provision for the situation where the improbable occurs and an
unintended viable weight premature infant is born either because of
the errors implicit in estimating probability of survival from ges-
tational age determined before birth, or because of advances in the
care of premature infants that improve chances of survival at lower
weights
3. The potential consequences of these decisions for the health of other
infants and children of future generations.
12-2f
In general, the lower the prenatal gestational age cutoff for viability
before birth and the higher the weight cutoff for viability after birth, the
less likely is the chance of a discrepancy between prenatal prediction and
postnatal reality. For example, if nontherapeutic research is only permitted
on a fetus or premature of 23 weeks or less gestational age estimated by ultra-
sound head measurements, and an eleven chance in a million of survival is judged
to be the equivalent of no survival (a weight of less than 751 grams) , there is
little risk of a fetus judged to be nonviable by gestational age turning out to
be viable weight after birth. However, there is still the possibility of such
an infant surviving and two years from now the probability of survival of a
751-gram premature infant might be as good as the chances of survival of a
1001-gram infant today. If this were to happen, the postnatal level of viabil-
ity of a 751-gram infant would clearly be set too low and would need to be
readjusted.
Alternatively, if research is only permitted on a fetus of 22 weeks or less
gestational age estimated prenatally by ultrasound, and zero chance of survival
in 1 million (less than 601 grams) is defined as the weight level of viability,
there is very little, if any, risk of a fetus judged to be nonviable before birth
turning out to be of a viable weight after birth. The need to readjust the weight
level of viability w'ithin two years is much less likely. However, progress in
clinical measures directed at improving survival and the quality of survival in
heavier premature infants (those above 600 grams) might be impeded by not having
the potential benefit of these measures being tried out first on abortuses who
could not have survived. It is likely that the first application of some poten-
tial advance for human infants first will have to be tested on some sick infants
who have a real chance of survival without the innovations. This means a certain
number of premature infants are likely to be harmed or not survive who might have
survived or not been injured if the new treatment had been studied on a fetus of
22-24 weeks gestation or an infant of less than 601 grams.
Finally, whatever the gestational age and weight cutoffs for viability,
there is always a chance in the future that a viable infant by weight will be
born after a prediction of nonviability by gestational age. When this occurs,
the premature infant clearly must be cared for in accord with accepted medical
care practice. For example, a mother who wants and is legally entitled to an
abortion at 24 weeks gestation should be informed of the possibility of fetal
survival before the abortion and either she must accept the responsibility for
a liveborn viable infant or make arrangements for placement or adoption. Further,
the physician should be protected from civil liability to the pregnant woman on
whom the abortion is performed for unintentially delivering her of a liveborn
viable premature infant.
In summary, the following might be considered as a reasonable way of pro-
ceeding in terms of the biologic facts and should be taken into consideration in
formulating public policy.
1. Before birth, permit research on a fetus of estimated gestational
age of 23 weeks or less.
12-29
2. After birth, permit research on a product of conception of less
than 601 grams and 24 weeks or less gestational age by physical
examination.
3. Set up an administrative mechanism to review No. 1 and No. 2 at
regular yearly intervals.
4. State that a physician performing an sibortion at 24 weeks should
inform the pregnant woman that there is a chance of a survival of
the abortus and that, if it is born at a viable weight and gesta-
tional age, it will be resuscitated. In this instance, protect
the physician from a civil cause of action by the pregnant woman
for delivery of a viable infant she did not want.
BIBLIOGRAPHY
1. Adams, F.H.; Fujiwara, T. ; Spears, R. ; and Hodgman, J., "Temperature Regu-
lation in Premature Infants," Pediatrics , April 1964.
2. Adamsons , K. , Myers, R.E., "Perinatal Asphyxia; Causes, Detection and
Neurologic Sequelae," Pediatrics Clinics of North America 20 (No. 2) :465-81 ,
May 1974.
3. Alden, E.R. ; Kalina, R.E.; and Hodson, W.A. , "Transient Cataracts in Low-
Birth-Weight Infants," Fetal and Neonatal Medicine 82 (No. 2) : 314-318.
4. Alden, E.R. ; Mandelkorn, T. ; Woodrum, E.E.; Wennburg, R.P.; Parks, C.R. ;
and Hodson, W.A. , "Morbidity and Mortality of Infants Weighing Less Than
1,000 Grams In An Intensive Care Nursery," Pediatrics 50 (No.l), July 1972.
5. Alford, C.A., Jr., "Immunoglobulin Determinations in the Diagnosis of Fetal
Infection," Pediatric Clinics of North America 18: February 1971.
6. Altshulder, G. , "Immunologic Competence of the Immature Human Fetus,"
Obstetrics and Gynecology 43: June 1974.
7. Amiel-Tison, C. , "Neurological Evaluation of the Maturity of Newborn Infants,'
Archives of Disease in Childhood 43:89-93, 1968.
8. Baden, M. ; Bauer, C.R. ; Colle, E.; Klein, G. ; Papageorgou, A.; and Stern, L. ,
"Plasma Cortiocosteroids in Infants with the Respiratory Distress Syndrome,'
Pediatrics 52: December 1973.
9. Balis, J.J., and Shelley, S.A., "Quantitative Evaluation of the Surfactant
System of the Lung," Annals of Clinical Laboratory Science 2: 1972.
10. Battaglia, F., Frazier, T.M., and Hellegers, A.E., "Birth Weight, Gestational
Age, and Pregnancy Outcome, with Special Reference to High Birth Weight-
Low Gestational Age Infant," Pediatrics 37: March 1966.
11. Battaglia, F.C., and Lubchenco, L.O. , "A Practical Classification of Newborn
Infants by Weight and Gestational Age," Journal of Pediatrics 71:159-163,
August 1967.
12. Bauer, C.R. , Stern, L. , and Colle, E., "Prolonged Rupture of Membranes Asso-
ciated with a Decreased Incidence of Respiratory Distress Syndrome,"
Pediatrics 53: January 1974.
12-31
BIBLIOGRAPHY (Continued)
13. Beard, R.W. , "The Detection of Fetal Asphyxia in Labor," Pediatrics 53:
February 1974.
14. Beard, R.W. , Morris, E.D., and Clayton, S.C., "pH of Foetal Capillary Blood
as an Indicator of the Condition of the Foetus," Journal of Obstetrics
and Gynaecology of the British Commonwealth 74:812-22.
15. Behrman, R.E., Neonatology: Diseases of the Fetus and Infant, St. Louis,
Mo.: The C.V. Mosby Company, 1973, pp. 1-60, 99-117, 218-232.
16. Behrman, R.E. , "The Use of Acid-Base Measurements in the Clinical Evaluation
and Treatment of the Sick Neonate," Journal of Pediatrics 74:632-21 ,
April 1969.
17. Behrman, R.E., Babson, G.S., and Lessel, R. , "Fetal and Neonatal Mortality
in White Middle Class Infants," American Journal of Diseases of
Children 121: June 1971.
18. Behrman, R.E.; James, L.S.; Klaus, M. ; Nelson, N. ; and Oliver, T. , "Treat-
ment of the Asphyxiated Newborn Infant," Journal of Pediatrics 74:981-88,
June 1969.
19. Bjerkedal, T. , Bakketeig, L. , and Lehmann, E.G., "Percentiles of Birth
Weights of Single Live Births at Different Gestation Periods," Acta
Paediatrica Scandinavica 62:449-457, 1973.
20. Bjerre, I., and Ostberg, G., "Infant Mortality," Acta Paediatrica Scandi-
navica 63:49-58, 1974.
21. Blumenfeld, T.A. , and Driscoll, J.M. , Jr., "Lecithin/Sphingomyeline Ratios
in Tracheal and Pharyngeal Aspirates in Respiratory Distress Syndrome,"
Journal of Pediatrics 85:403-407, September 1974.
22. Bolton, D.P., and Gross, K.W. , "Further Observations on Cost of Preventing
Retrolental Fibroplasia," The Lancet, March 16, 1974.
23. Boothby, R.J. , "Florida Neonatal Intensive Care Program," Journal of the
Florida Medical Association 60: May 1973.
24. Bryan, M.H.; Hardie, M.J.; Reilly, B.J.; and Suyer, M.B., "Pulmonary
Function Studies During the First Year of Life in Infants Recovering From
the Respiratory Distress Syndrome," Pediatrics 52: August 1973.
25. Buist, N.R.M., and Jhaveri, B.M. , "A Guide to Screening Newborn Infants
for Inborn Errors of Metabolism," Journal of Pediatrics 82:511-522, 1973.
26. Burnard, E . ; Grattan-Smith, P.; Picton-Warlow, G. ; and Grauaug, A.,
"Pulmonary Insuffiency in Prematurity," Australian Paediatric Journal 1:12,
1965.
12-32
BIBLIOGRAPHY (Continued)
27. Cahill, J., Cohen, H., and Starkovsky, N. , "A Rapid Screening Test for
Detection of Alpha-1 Fetoprotein as an Indicator of Fetal Distress,"
American Journal of Obstetrics and Gynecology 119:1095-1100, August 15, 1974.
28. Campbell, S., and Newman, G.B., "Growth of the Fetal Biparietal Diameter
During Normal Pregnancy," Journal of Obstetrics and Gynaecology of the
British Commonwealth 78:513-19, June 1971.
29. Castelman, B., Scully, R.E., and McNeely, B.U. , "Case Records of the
Massachusetts General Hospital Weekly Clinicopathological Exercises,"
The New England Journal of Medicine, March 7, 1974.
30. Catz , C, and Yaffe, S.J., "Barbituate Enhancement of Bilirubin Conjugation
and Excretion in Young and Adult Animals," Pediatrics 2:361-370, 1968.
31. Chabot, A., "Improved Infant Mortality Rates in a Population Served by A
Comprehensive Neighborhood Health Program," Pediatrics 47: June 1971.
32. Chase, H.C., "Infant Mortality and Weight at Birth: 1960 U.S. Birth Cohort,"
American Journal of Public Health 59: September 1969.
33. Chase, H.C., "Ranking Countries by Infant Mortality Rates," Public Health
Reports 84: January 1969.
34. Cheek, J.A. , Jr., and Staub, G.F., "Nasojejunal Alimentation for Premature
and Full-Term Newborn," The Journal of Pediatrics 82:955-962.
35. Chernick, V., and Vidyasagar, D. , "Continuous Negative Chest Wall Pressure
in Hyaline Membrane Disease: One Year Experience," Pediatrics 49: May 1972.
36. Chernick, V., "Hyaline Membrane Disease - Therapy with Constant Lung-Distending
Pressure," The New England Journal of Medicine, August 9, 1973.
37. Christie, G. , and Gudmore, D. , "The Oxytocin Challenge Test," American Journal
of Obstetrics and Gynecology 118:327-330, February 1974.
38. Clark, C.A. , "The Prevention of Rh Isoimmunization," Hospital Practice,
January 1973.
39. Commentary: "Standards for Birth Weight or Intrauterine Growth," Pediatrics 4&:
July 1970.
40. Cornblath, M. ; Forbes, A.E. ; Pildes, R.S.; Luebben, G.; Greengard, J., "A
Controlled Study of Early Fluid Administration on Survival of Low Birth
Weight Infants," Pediatrics 38:547-53, October 1966.
41. Cremer, R. ; Lond, M.B. ; Perryman, P.W.; Richards, D.H. , "Influence of Light
on the Hyperbilirubinanemia of Infants," The Lancet, May 1958.
12-33
BIBLIOGRAPHY (Continued)
42. Crichton, J.U.; Dunn, H.G.; McBurney, A.; Robertson, A.; and Tredger, E.,
"Long-Term Effects of Neonatal Jaundice on Brain Function in Children
of Low Birth Weight," Pediatrics 49: May 1972.
43. Crichton, J.U. ; Dunn, H.G.; McBurney, K. ; Robertson, A.; and Tredger, E.,
"Minor Congenital Defects in Children of Low Birth Weight," Journal of
Pediatrics, May 1972.
44. Cushner, I.M., and Mellits, E.D., "The Relationship Between Fetal Outcome
and the Gestational Age and Birth Weight of the Fetus," Hopkins Medical
Journal 128: May 1971.
45. Dahm, L.S., and James, L.S., "Newborn Temperature and Calculated Heat Loss
in the Delivery Room," Pediatrics 49: April 1972.
46. Dann, M. , Levine, S.Z., and New, E.V., "A Long-Term Follow-up Study of Small
Premature Infants," Pediatrics , June 1964.
47. Davison, J.M. ; Lind, T. ; Farr , V.; and Whittingham, T.A. , "The Limitations
of Ultrasonic Fetal Cephalometry ," Journal of Obstetrics and Gynaecology
of the British Commonwealth 80:769-75, September 1973.
48. Dawes, G.S., "Revolutions and Cyclical Rhythms in Prenatal Life: Fetal
Respiratory Movements Rediscovered," Pediatrics 51: June 1973.
49. Dignam, W.J. , "Fetal Survival with Premature Delivery in Complications of
Pregnancy," American Journal of Obstetrics and Gynecology 98: July 1967.
50. Dobbing, J., and Sands, J., "Quantitative Growth and Development of Human
Brain," Archives of Disease in Childhood 48:757, 1973.
51. Donahue, C.L., and Wan, T.H., "Measuring Obstetric Risks of Prematurity:
A Preliminary Analysis of Neonatal Death," American Journal of Obstetrics
and Gynecology 116:911-915, August 1973.
52. Dreyfus-Brisac, C. , "The Electroencephalogram of the Premature Infant,''
World Neurology 3, Minneapolis, January 1952.
53. Dreyfus-Brisac; Samson, C. ; Blanc, C. ; and Monod, N. , "L'Electroencephalo-
gramme De L 'Enfant Normal De Moins De 3 Ans," Etudes Neo-Natales VII: 1958.
54. Driscoll, J.M. ; Heird, W.C.; Shullinger, J.N. ; Gongaware, R.D.; and
Winters, R.W. , "Total Intravenous Alimentation in Low-Birthweight Infants:
A Preliminary Report," Journal of Pediatrics 81:145-153, July 1972.
55. Dubowitz, A.M.V. , "Assessment of Gestational Age in Newborn Infants: Nerve
Conduction Velocity Versus Maturity Score," Developmental Medicine and
Child Neurology 14:290-5, 1972.
BIBLIOGRAPHY (Continued)
56. Due, G.V. , and Cumarasamy , N. , "Digital Arteriolar Oxygen Tension as a
Guide to Oxygen Therapy of the Newborn," Biology of the Neonate 24:134-7,
1974.
57. Dunn, P.M., "Methodology of Reporting and Analysis of Perinatal Morbidity
and Mortality," World Health Organization, Geneva, April 30-May 6, 1974.
58. Dunn, P.M. , "Localization of the Umbilical Catheter by Post-Mortem Measure-
ment," American Journal of Diseases of Children 41:69, 1966.
59. Durkan, J.P. , and Russo, G.L., "Ultrasonic Fetal Cephalometry : Accuracy,
Limitations, and Applications, Obstetrics and Gynecology 27:399-403,
March 1966. • • . , - • .
60. Dweck, H.S. ; Saxon, J.; Benton, W. ; and Cassady, G. , "Early Development of
the Tiny Premature Infant," American Journal of Diseases of Children 126,
July 1973.
61. Eaves, L.C.; Nuttall, C; Klonof f , H. ; and Dunn, G.H. , "Developmental and
Psychological Test Scores in Children of Low Birth Weight," Pediatrics 45,
January 1970.
62. Engel, R. , "Maturational Changes and Abnormalities in the Newborn Electro-
encephalogram," Developmental Medicine and Child Neurology 7:498-506, 1965.
63. Erkan, N.V. , Stark, C.R. , and Cardany, G. , "An Evaluation of Newborn
Mortality and Prematurity Trends at Columbia Hospital for Women,"
Washington, D.C., Medical Annals of the District of Columbia 41: March 1972.
64. Fanaroff, A.A. ; Cha, C.C; Sosa, R. ; Crumrine, R.S.; and Klaus, M.H. ,
"Controlled Trial of Continuous Negative External Pressure in the Treat-
ment of Severe Respiratory Distress Syndrome," Journal of Pediatrics 82:
921-928, June 1973. . - . _ . ■.•. .^. ,.
65. Fedrick, J., "Neonatal Deaths, Time of Death, Maturity, and Lesion,"
Biology of the Neonate 18:369-378, 1971.
56. Fedrick, J., and Butler, N., "Certain Causes of Neonatal Death," Biology
of the Neonate 15:229-255, 1970.
67. Feins, N.R., "Pediatric Surgery," Pediatric Clinics of North America 21 (No. 2)
May 1974. .
68. Filler, R.M. ; Eraklis, A. J. ; Rubin, V.G.; and Das, J.B., "Long-Term Total
Parenteral Nutrition in Infants," The New England Journal of Medicine 281,
September 1969.
69. Finnstrom, 0., "Studies on Maturity in Newborn Infants," Acta Paediatrica
Scandinavica 61:24-41, 1972.
12-35
BIBLIOGRAPHY (Continued)
70. Fitzhardinge, P., and Ramsay, M. , "The Improving Outlook for the Small
Prematurely Born Infant," Developmental Medicine and Child Neurology 15:
447-459, August 1973.
71. Fitzhardinge, P., and Steven, E.M., "The Small-for-Date Infant,
II. Neurological and Intellectual Sequelae," Pediatrics 50: July 1972.
72. Fox, J.H.; Fishman, M.A. ; Dodge, P.R.; and Prensky, A.I., "The Effect of
Malnutrition of Human Central Nervous System Myelin," Neurology 22:
December 1972.
73. Frasier, S.D., Weiss, B.A. , and Morton, R. , "Amniotic Fluid Testosterone:
Implications for the Prenatal Diagnosis of Congenital Adrenal Hyperplasia,"
The Journal of Pediatrics 84:7 38-741, May 1974.
74. Gartner, L.M. ; Snyder, R.N. ; Chabon, R.S.; and Bernstein, J., "Kernicterus ,
High Incidence in Premature Infants with Low Serum Bilirubin Concentrations,"
Pediatrics 45:906-917, June 1970.
75. Gauthier, G. , Jr., Desjardins, P., and McLean, F., "Fetal Maturity: Amniotic
Fluid Analysis Correlated with Neonatal Assessment," American Journal of
Obstetrics and Gynecology 112:344-350, February 1972.
76. Geijerstam, G. , "Low Birth Weight and Perinatal Mortality," Public Health
Reports 84: November 1969.
77. Ghosh, S., and Daga, S., "Comparison of Gestational Age and Weight as
Standards of Prematurity," Journal of Pediatrics 71:173-175, August 1967.
78. Glass, L. , Kolko, N., and Evans, H., "Factors Influencing Predisposition to
Serious Illness in Low Birth Weight Infants," Pediatrics 48: September 1971.
79. Gleichert, J.E., "Patterns in Perinatal Mortality," American Journal of
Obstetrics and Gynecology , July 1970.
80. Gluck, L. , and Kulovich, M.V. , "Lecithin/Sphingomyelin Ratios in Amniotic
Fluid in Normal and Abnormal Pregnancy," American Journal of Obstetrics
and Gynecology 115:539-546, February 1973.
81. Gluck, L. , "Pulmonary Surfactant and Neonatal Respiratory Distress,"
Hospital Practice, November 1971.
82. Gray, O.P. , Ackerman, A., and Fraser, A. J. , "Intracranial Haemorrhage and
Clotting Defects in Low-Birth-Weight Infants," Lancet, March 1968,
pp. 545-48,
83. Gregory, G.A. ; Kitterman, J.A. ; Phibbs, R.H. ; Tooley, W.H.; and Hamilton, W.K. ,
"Treatment of the Idiopathic Respiratory Distress Syndrome with Continuous
Positive Airway Pressure," The New England Journal of Medicine 294, June 1971.
12-36
BIBLIOGRAPHY (Continued)
84. Gruenwald, P., American Journal of Obstetrics and Gynecology 94:1112-1119,
1966.
85. Gruenwald, P., "Infants of Low Birth Weight Among 5,000 Deliveries,"
Pediatrics 34: August 1964.
86. Gupta, J.M. ; Van Vliet, J.; Vonwiller, J.; Abrahams, N.; and Fisk, G.C. ,
"Positive Airway Pressure in Respiratory Distress Syndrome," Medical
Journal of Australia 1:90-94, 1974.
87. Gyepes, M. , and Vincent, W.R. , "Severe Congenital Heart Disease in the
Neonatal Period: A Functional Approach to Emergency Diagnosis," American
Journal of Roentgenology , Radium Therapy and Nuclear Medicine 116:
November 1972.
88. Hamilton, L.A. , Jr., Szujewski, P.F., and Patel , M.K. , "Combined Sonographic
and Biochemical Estimation of Fetal Maturity in High-Risk Pregnancy,"
Obstetrics and Gynecology 41: June 1973.
89. Harper, P. A., and Wiender, G. , "Sequelae of Low Birth Weight," Annual Review
of Medicine 16:405-420, 1965.
90. Harrod, J.R. ; L'Heureux, P.; Wangensteen, O.D.; and Hunt, C.E., "Long Term
Follow-Up of Severe Respiratory Distress Syndrome Treated with IPPB,"
Journal of Pediatrics 84:277-286, February 1974.
91. Hellman, L.M. ; Kobayashi , M. ; Fillisti, L. ; Lavenhar , M. , "Sources of Error
in Sonographic Fetal Mensuration and Estimation of Growth," American
Journal of Obstetrics and Gynecology 99:662-70, November 1967.
92. Hellman, L.M. , Kobayashi, M. , and Cromb, E., "Ultrasonic Diagnosis of
Embryonic Malformations," American Journal of Obstetrics and Gynecology 115 ;
615-623, March 1973.
93. Helmrath, T.A. , Hodson, W.A. , Oliver, T.K. , Jr., "Positive Pressure Venti-
lation in the Newborn Infant: The Use of a Face Mask," Journal of
Pediatrics 16:202-201 , February 1970.
94. Hendren, W.H. , "Pediatric Surgery," New England Journal of Medicine 289:
456-462, 507-515, 562-568, August 30, September 6, September 13, 1973.
95. Hey, E.N., and Katz , G. , "The Optimum Thermal Environment for Naked
Babies," Archives of Disease in Childhood 45:328, 1970.
96. Hirvensalo, M. , and Arko, H. , "Studies in Perinatal Mortality in a Large
Maternity Hospital," Annales Paediatriae Fenniae 13:46-55, 1967.
12-37
BIBLIOGRAPHY (Continued)
97. Hobbins , J.C., Mahoney, M.J., and Goldstein, L. , "New Methods of Intrauterine
Evaluation by the Combined Use of Fetoscopy and Ultrasound," American
Journal of Obstetrics and Gynecology 118:1069-1072, 1974.
98. Hobbins, J.C., and Mahoney, M.D. , "In Utero Diagnosis of Hemoglobinopathies,"
Medical Intelligence 290.
99. Hobel, C. ; Oh, W. ; Hyvarinen , M.A. ; Emmanouilides , G.C., and Erenberg, A.,
"Early Versus Late Treatment of Neonatal Acidosies in Low-Birth-Weight
Infants: Relation to Respiratory Distress Syndrome," Journal of
Pediatrics 81:1178-1187, December 1972.
100. Huch, A.; Huch, R. ; Neumayer , E.; and Rooth, G. , "Continuous Intra-Arterial
p02 Measurements in Infants," Acta Paediatrica Scandinavica 61:722-23, 1972.
101. Hunt, C.E. , "The High Risk Newborn, Management and Outcome of Prematurity,
Respiratory Distress Syndrome (RDS) and Other Major Neonatal Problems,"
Minnesota Medicine , May 1974.
102. Ikonen, R.S., and Lauslahti, K. , "Apgar Scoring and Neonatal Morbidity in
Infants Weighing 1000-1990 g," Annals of Clinical Research 5:161-194, 1974.
103. Ingraham, H., "Vital Statistics of New York State," State Department of
Health, 1973.
104. Insler, V.; Bernstein, D.,- Rikover, M. ; and Segal, T., "Estimation of Fetal
Weight In Utero by Simple External Palpation," American Journal of
Obstetrics and Gynecology, May 1967.
105. "Intensive Care of the Newborn," Lancet, May 1974, p. 969.
106. Israel, R. , and Klebba, A.J., "A Preliminary Report on the Effect of Eighth
Revision ICDA on Cause of Death Statistics," American Journal of Public
Health 59: September 1969.
107. James, L.S., and Morishima, H.O., "Mechanism of Late Deceleration of the
Fetal Heart Rate," International Journal of Gynecology and Obstetrics 10,
1972.
108. Jensen, A.; Josso, F. ; Zamet, P.; Monset-Couchard, M. ; and Minkowski, A.,
"Evolution of Blood Clotting Factor Levels in Premature Infants During
the First 10 Days of Life: A Study of 96 Cases with Comparison Between
Clinical Status and Blood Clotting Factor Levels," Pediatric Research 1 :
638-644, 1973.
109. Johnson, J.D.; Malachowski, N.C. ; Grobstein, R. ; Welsh, D. ; and Sunshine, P.,
"Prognosis of Children Surviving with the Aid of Mechanical Ventilation
in the Newborn Period," Journal of Pediatrics 84:272-276, February 1974.
BIBLIOGRAPHY (Continued)
110. Kan, Y.W. ; Dozy, A.M.; Alter, B.P.; Frigoletto, F.D.; and Nathan, D.G.,
"Detection of the Sickle Gene in the Human Fetus," New England Journal
of Medicine 287: July 1972.
111. Kaplan, E.; Herz , F. ; Scheye , E.; and Robinson, L.D., Jr., "Phototherapy
in ABO Hemolytic Disease of the Newborn Infant," Journal of
Pediatrics 79:911-914, December 1971.
112. Kenny, J. P., Boesman, M.I., and Michaels, R.H. , "Bacterial and Viral
Coproantibodies in Breast-Fed Infants," Pediatrics 39: February 1967.
113. Kessler, A.D. , Reichelderf er , T.E., and Scott, R.B., "Trends in Neonatal
Mortality Among Nonwhite Infants in the District of Columbia," Medical
Annals of the District of Columbia, November 1957.
114. Kildeberg, P., "Disturbances of Hydrogen Ion Balance Occuring in Premature
Infants," Acta Paediatrica 53:517-526, November 1964.
115. Kitchen, W.H., and Campbell, D.G., "Controlled Trial of Intensive Care for
Very Low Birth Weight Infants," Pediatrics 48:5, November 1971.
116. Kitterman, J.A. ; Edmunds, H. , Jr.; Gregory, G.A. ; Heymann, M.A. ; Tooley, W.H.
and Rudolph, A.M., "Patent Ductus Arteriosus in Premature Infants," New
England Journal of Medicine 287:10, 1972.
117. Kohorn, E.I., and Pritchard, J.W. , "The Safety of Clinical Ultrasonic
Examination," Obstetrics and Gynecology 29 -.212-21 A, February 1967.
118. Koivisto, M. , Blanco-Sequeiros , M. , and Krause , U., "Neonatal Symptomatic
and Asymptomatic Hypoglycaemia : A Follow-Up Study of 151 Children,"
Developmental Medicine and Child Neurology 14:603-614, 1972.
119. Kotas, R.V. , Fazen, L.E., and Moore, T.E., "Umbilical Cord Serum Trypsin
Inhibitor Capacity and the Idiopathic Respiratory Distress Syndrome,"
Journal of Pediatrics 81:593-599.
120. Lamarre, A.; Linsao, L. ; Reilly, B.J.; Swyer , P.R.; and Levison, H.,
"Residual Pulmonary Abnormalities in Survivors of Idiopathic Respiratory
Distress Syndrome," American Review of Respiratory Disease 108: 1973.
121. "The Price of Perinatal Neglect," Lancet, 1974.
122. Lappe, M. , Gustafson, J.M., and Roblin, R. , "Ethical and Social Issues in
Screening for Genetic Disease," Screening for Genetic Disease - a Group
Report 286.
123. Leopold, G.R. , and Asher , M.W. , "Ultrasound in Obstetrics and Gynecology,"
Radiologic Clinics of North America 12: April 1974.
12-39
BIBLIOGRAPHY (Continued)
124. Levitsky, S. , and Hastreiter, A.R., "Cardiovascular Surgical Emergencies
in the First Year of Life," Surgical Clinics of North America 52,
February 1971.
125. Liggins, G.C., and Howie, R.M. , "A controlled Trial of Antepartum Gluco-
corticoid Treatment for Prevention of the Respiratory Distress Syndrome
in Premature Infants," Pediatrics 50: October 1972.
126. Lubchenco, L.O.; Bard, H.; Goldman, A.L.; Coyer, W.E.; Mclntyre, C. ; and
Smith, D.M. , "Newborn Intensive Care and Long-Term Prognosis," Develop-
mental Medicine and Child Neurology 16:421-431, August 1974.
127. Lubchenco, L. , Boyd, E., and Hansman, C, "Intrauterine Growth in Length
and Head Circumference as Estimated from Live Births at Gestational
Ages from 26 to 42 Weeks," Pediatrics 37: March 1966.
128. Lubchenco, L.O., Delivoria-Papadopoulos , M. , and Searls, D. , "Long-Term
Follow-Up Studies of Prematurely Born Infants. I. Relationship of
Handicaps to Nursery Routines," Journal of Pediatrics 80:501-508,
March 1972.
129. Lubchenco, L.O.; Delivoria-Papadopoulos, M. ; Butterfield, L.J. ;
French, J.H.; Metcalf, D. ; Hix, I.E.; Danka, J.; Dodds, J.; Downs, M;
and Freeland, E., "Long-Term Follow-Up Studies of Prematurely Born
Infants. II. Influence of Birth Weight and Gestational Age on Sequelae,"
Journal of Pediatrics 80:509-512, March 1972.
130. Lubchenco, L.O. , Searls, D.T., and Brazie, J.V. , "Neonatal Mortality
Rate: Relationship to Birth Weight and Gestational Age," Journal of
Pediatrics 81:814-822.
131. Lucey , J., Ferreiro, M. , and Hewitt, J., "Prevention of Hyperbilirubinemia
of Prematurity by Phototherapy," Pediatrics 41: June 1968.
132. Mann, L.I., and Duchin , S., "Fetal EEG Sleep Stages and Physiologic
Variability," American Journal of Obstetrics and Gynecology 119:533-538,
June 1974.
133. Malan, A.F.; Evans, A.; Heese , H. ; and De V., "Serial Acid-Base Determina-
tions in Normal Premature and Full-Term Infants During the First 72 Hours
of Life," Archives of Disease in Childhood 40:645-650, 1965.
134. Markarian, M. ; Githen, J.H. ; Rosenblut, E.; Fernandez, F.; Jackson, J. ;
Bannon, A.; Lindley, A.; Lubchenco, L. ; and Martorell , R. , "Hyper-
coagulability in Premature Infants with Special Reference to the
Respiratory Distress Syndrome and Hemorrhage," Biology of the
Neonate 17:84-97, 1971.
12-40
BIBLIOGRAPHY (Continued)
135. Martin, C.B.; Murata, Y.; Petrie, R.H. ; and Parer, J.T., "Respiratory
Movements in Fetal Rhesus Monkeys," /American Journal of Obstetrics and
Gynecology 119: August 1974.
136. Melhorn, D.K. , and Gross, S., "The Red Cell Hydrogen Peroxide Hemolysis
Test and Vitamin E Absorption in the Differential Diagnosis of Jaundice
in Infancy," Journal of Pediatrics 81:1082-1087, December 1972.
137. Mendicini, M. ; Scalamandre, A.; Savignoni, P.O.; Piceci-Bucci , S.;
Esuperanzi, R. ; and Bucci, G. , "A Controlled Trial on Therapy for New-
borns Weighing 750-1250 Grams," Acta Paediatrica Scandinavica 60:407-416,
1971.
138. Miller, H.C., and Hassanein, K. , "Diagnosis of Impaired Fetal Growth in
Newborn Infants," Pediatrics 48: October 1971.
139. Milunsky, A., Clinics in Perinatology, vol. 1, no. 2, Philadelphia: W.B.
Saunders, Co., September 1974, pp. 229-252, 273-320, 321-330, and
507-526.
140. Milunsky, A., Alpert , E., and Charles, D. , "Amniotic Fluid Alpha-Fetoprotein
in Anencephaly , " Obstetrics and Gynecology 43: April 191 A.
141. Milunsky, A.; Littlefield, J.W.; Kanf er , J.N.; Kolodny, E.H.; Shih, V.E.;
and Atkins, L. , "Prenatal Genetic Diagnosis," New England Journal of
Medicine, Part 1 . , 283 (25) :1370-80, 1970; Part 2, 283 (26) : 1441-46, 1970;
Part 3, 283(27) :1498-1508, 1970.
142. Monond, N., Pajot, N., and Guidasci, S., "The Neonatal EEG : Statistical
Studies and Prognostic Value in Full-Term and Pre-Term Infants," Electro-
encephalography and Clinical Neurophysiology 32:529-544, 1972.
143. Monro, J.S., "A Premature Infant Weighing Less Than One Pound at Birth and
Survived and Developed Normally," Canadian Medical Association Journal
40:69-70, 1939.
144. Moriyama, I.M., "Present Status of Infant Mortality Problem in the U.S.,"
Public Health Reports 75:391-405, May 1960.
145. Mountain, K.R. , Hirsh, J., and Gallus, A.S., "Neonatal Coagulation Defect
Due to Anticonvulsant Drug Treatment in Pregnancy," Lancet, pp. 265-8,
February 1970.
146. Muxworthy, S.M., "Capillary Methods for Screening Coagulation Defects in
the Newborn Baby," Medical Laboratory Technology 29:48-50, 1972.
147. Naeye, R.L. , and Blanc, W.A., "Fetus, Placenta, and Newborn," American
Journal of Obstetrics and Gynecology, August 1973.
12-41
BIBLIOGRAPHY (Continued)
148. Naeye, R.L. ; Burt, L.S.; Wright, B.S.; Blanc, W.A. ; and Tatter, D.,
"Neonatal Mortality, the Male Disadvantage," Pediatrics 48: December 1971.
149. Naeye, R.L. , Harcke, H.T. , and Blanc, W.A. , "Adrenal Gland Structure and
the Development of Hyaline Membrane Disease," Pediatrics 47: April 1971.
150. Nielsen, N., "Coagulation and Fibrinolysis in Prematurely Delivered Mothers
and their Premature Infants," Acta Obstetricia et Gynecologica
Scandinavica 48:505-25, 1969.
151. Nesbit, R. , Clinics in Perinatology, vol. 1, no. 1, Philadelphia: W.B.
Saunders, Co., March 1974, pp. 3-18, 125-140, 149-172.
152. Niswander, K.R., Capraro, V. J. , and Van Coevering, R.J., "Estimation of
Birth Weight by Quantified External Uterine Measurements," Obstetrics
and Gynecology 36: August 1970.
153. Noonan, CD., "Antenatal Diagnosis of Fetal Abnormalities," Radiologic
Clinics of North America 12: April 1974.
154. Northway, W.H., Jr., Rosan, R.C., and Porter, D.Y., "Pulmonary Disease
Following Respirator Therapy of Hyaline-Membrane Disease," New England
Journal of Medicine 276: February 1967.
155. Oh, W. ; Arbit, J.; Blonsky, E.R.; and Cassell, S., "Neurologic and
Psychometric Follow-Up Study of Rh-erythroblastotic Infants Requiring
Intrauterine Blood Transfusion," American Journal of Obstetrics and
Gynecology: June 1971.
156. Omenn, G.S.; Figley, M.M. ; Graham, C.B.; and Heinrich, L.W., "Prospects
for Radiographic Intrauterine Diagnosis - the Syndrome of Thrombocytopenia
with Absent Radii," Medical Intelligence 288.
157. Omer, M. , Robson , E., and Neligan, G. , "Can Initial Resuscitation of Pre-
term Babies Reduce the Death Rate from Hyaline Membrane Disease,"
Archives of Disease in Childhood 49:219, 1974.
158. Organ, L.W. ; Milligan, J.E.; Goodwin, J.W.; and Bain, M.J.C., "The Pre-
Ejection Period of the Fetal Heart: Response to Stress in the Term Fetal
Lamb," American Journal of Obstetrics and Gynecology 115:377-386,
February 1973.
159. Outerbridge, E., Roloff, D.W. , and Stern, L. , "Continuous Negative Pressure
in the Management of Severe Respiratory Distress Syndrome," Journal of
Pediatrics 81:398-391, August 1972.
160. Paediatric Research Society, 18th Meeting, St. Mary's Hospital, Manchester,
March 1971, Archives of Disease in Childhood 46:736.
BIBLIOGRAPHY (Continued)
161. Panagopoulos , G. , Valaes, T. , and Doxiadis, S.A., "Morbidity and Mortality
Related to Exchange Transfusions," Journal of Pediatrics 74: February 1959.
162. Parmelee, A.H., Jr.; Minkowski, A.; Dargassies, S . ; Dreyfus-Brisac , C.;
Lezine, I.; Berges, J.; Chervin, G.; and Stern, E., "Neurological Evalu-
ation of the Premature Infant," Biology of the Neonate 15:55-78, 1970.
163. Parmelee, A.H., and Schulte, F.J., "Development and Testing of Pre-Term
and Small for Date Infants," Pediatrics 45, No. 1, Part 1, January 1970.
164. Paul, R.H. , and Hon, E.H., "Clinical Fetal Monitoring V. Effect on Perinatal
Outcome," American Journal of Obstetrics and Gynecology 118:529-53 3,
February 1974.
165. Peden, V.H., and Karpel, J., "Total Parenteral Nutrition in Premature
Infants," Journal of Pediatrics 81:137-144, July 1972.
165. Phibbs, R.H.; Johnson, P.; Kitterman, J. A.,- Gregory, G.A.; and Tooley,W.H.,
"Cardiorespiratory Status of Erythoblastic Infants," Pediatrics 49:5-14,
January 1972 .
167. Phibbs, R.H. ; Johnson, P.; Tooley, W.H.; Johnson, B.B.; Sudman , D.; and
Schlueter, M. , "Cardiorespiratory Status of Erythoblastotic Newborn
Infants: II. Blood Volume, Hematocrit, and Serum Albumin Concentration
in Relation to Hydrops Fetalis," Pediatrics 53: January 1974.
168. Pildes, R.S.; Cornblath , M. ; Warren, I.; Page-El, di Menza; Merritt , D.M.;
and Peeva, A., "A Prospective Controlled Study of Neonatal Hypoglycemia,"
Pediatrics 54: July 1974.
169. Potter, E.D., and Davis, M.E., "Perinatal Mortality," American Journal of
Obstetrics and Gynecology 105:335-348, October 1969.
170. Powell, L.C., Jr., and Schreiber, M.H., "Intrauterine Fetal Transfusion,"
Radiologic Clinics of North America 12: April 1974.
171. Prod'hom, S.L.; Levison, H. ; Cherry, R.B.; Smith, C.A., "Adjustment of
Ventilation, Intrapulmonary Gas Exchange, and Acid-Base Balance During
the First Day of Life," Pediatrics 35:562-74, April 1965.
172. Purves, M.J. , "Onset of Respiration at Birth," Archives of Disease in
Childhood 49:333, 1974.
173. Ranlov, P., and Siggaard-Andersin , O. , "Late Metabolic Acidosis in Pre-
mature Infants," Acta Paediatrica Scandinavica 54:531-540, November 1955.
174. Rennard, M. , "Perinatal Mortality," American Journal of Obstetrics and
Gynecology: July 1969.
BIBLIOGRAPHY (Continued)
175. Reynolds, E.O.R. , and Taghizadeh, A., "Improved Prognosis of Infants
Mechanically Ventilated for Hyaline Membrane Disease," Archives of
Disease in Childhood 49:505-515, 1974.
176. Roback, S.A. ; Foker, J.; Frantz , I.E.; Hunt, C.E.; Engel , R.R.;
and Leonard, A.S., "Necrotizing Enterocolitis," Archives of
Surgery 109: August 1974.
177. Rosen, M.G., and Scibetta, J.J., "The Human Fetal Electroencephalogram.
2. Characterizing the EEC During Labor," Neuropadiatric 2 (No. 1): 1970.
178. Rubin, R.A. , Rosenblatt, C. , and Balow, B., "Psychological and Educational
Sequelae of Prematurity," Pediatrics 52 (No. 3) : September 1973.
179. Scherzer, A., and Mike, V., "Cerebral Palsy and the Low Birth Weight Child,
American Journal of Diseases of Children 128: August 1974.
180. Schulte, F.J. ; Michaelis, R. ; Linke, I.; and Nolte , R. , "Motor Nerve
Conduction Velocity in Term, Preterm, and Small for Dates Newborn
Infants," Pediatrics 42: July 1968.
181. "Fetal Research: The Case History of a Massachusetts Law,"
Science 187; December 1974.
182. Sherline, D.M. , and Thompson, J., "Continuous Cardiac Rate Monitoring
During Resuscitation of the Newborn Infant," American Journal of
Obstetrics and Gynecology 116:1166-1167, August 1973.
183. Silverman, W. , "Diagnosis and Treatment: Use and Misuse of Temperature
and Humidity in the Care of the Newborn Infant," Pediatrics: February 1964.
184. Sinclair, J.C., "Neonatal Acidosis and Respiratory Distress Syndrome in
the Preterm Infant: Role of Early PH Correction with Bicarbonate,"
Journal of Pediatrics 81:1188-1189, December 1972.
185. Sisson, T.R.C.; Kendall, N.; Glauder, S.C.; Knutson, S . ; and Sunyaviroch, E . ,
"Phototherapy of Jaundice in Newborn Infants. I. ABO Blood Group Incom-
patibility," Journal of Pediatrics 904: December 1971.
186. Smith, R.M. , "Diagnosis and Treatment: Nasotracheal Intubation as a
Substitute for Tracheostomy," Pediatrics 38:652-4, October 1966.
187. Sokol, R.J.; Rosen, M.G.; Borgsted , A.D.; Lawrence, R.A. ; and Steinbrecher , M.
"Abnormal Electrical Activity of the Fetal Brain and Seizures of the Infant,
American Journal of Diseases of Children 127: April 1974.
188. Stewart, Ann L. , and Reynolds, E.O., "Improved Prognosis for Infants of
Very Low Birthweight ," Pediatrics 54: December 1974.
BIBLIOGRAPHY (Continued)
189. Stone, M.L., Weingold, A.B., and Lee, B.O., "Clinical Applications of
Ultrasound in Obstetrics and Gynecology," American Journal of Obstetrics
and Gynecology 113:1046-1052, August 1972.
190. Stuart, J.; Picken, A.M.; Breeze, G.R. ; Wood, B.S.B., "Capillary-Blood
Coagulation Profile in the Newborn," Lancet, pp. 1467-71, December 1973.
191. Susser, M. , Marolla, F.A., and Fleiss, J., "Birth Weight, Fetal Age and
Perinatal Mortality," American Journal of Epidemiology 96:197-204, 1972.
192. Tabb, P. A.; Savage, D.C.L.; Inglis, J.; Walker, C.H.M., "Controlled Trial
of Phototherapy of Limited Duration in the Treatment of Physiological
Hyperbilirubinemia in Low Birth Weight Infants," Lancet 2 (No. 7789),
December 1972.
193. Tasang, R. ; Glu'eck, C.U.; Evans, G. ; and Steiner, P.M., "Cord Blood Hyper-
triglyceridemia," American Journal of Diseases of Children 127: January 1974.
194. Terris , M. , and Glasser, M. , "A Life Table Analysis of the Relation of
of Prenatal Care to Prematurity," American Journal of Public
Health 64: September 1974.
195. Thompson, J. P., "Some Observations on the Geographic Distribution of Pre-
mature Births and Perinatal Deaths in Indiana," American Journal of
Obstetrics and Gynecology : May 1968.
196. Usher, R. , McLean, F. , "Intrauterine Growth of Liveborn Caucasian Infants
at Sea Level: Standards Obtained from Measurements in 7 Dimensions
of Infants Born Between 25 and 44 Weeks of Gestation," Journal of
Pediatrics 74:901-910, June 1969.
197. U.S. Department of Health, Education and Welfare, "A Study of Infant
Mortality From Linked Records by Birth Weight, Period of Gestation, and
Other Variables, United States, 1960, Live-Birth Cohort," Rockville,
Maryland, 1972.
198. U.S. Department of Health, Education and Welfare, "Comparison of Neonatal
Mortality from Two Cohort Studies," Public Health Service, Rockville,
Maryland, June 1972.
199. Valdes-Dapena, M.A. , and Arey, J.B., "The Causes of Neonatal Mortality: An
Analysis of 501 Autopsies on Newborn Infants," Journal of
Pediatrics : September 1970. ,• .
200. Valenti, C. ; Lin, C.C.; Barnn, A.; Massobrio, M. ; Carbonara, A., "Pre- , ■
natal Sex Determination," American Journal of Obstetrics and
Gynecology 112: 890-5, April 1972.
12-45
BIBLIOGRAPHY (Continued)
201. Valman, H.B.; Heath, CD.; Brown, R.J.K., "Continuous Intragastric Milk
Feeds in Infants of Low Birth Weight," British Medical Journal 3:547-50,
September 1972.
202. van den Berg, B.J., "Morbidity of Low Birth Weight and/or Preterm Children
Compared to That of the 'Mature,'" Pediatrics 42: October 1968.
203. van den Berg, B.J., and Yerushalmy, J., "The Relationship of the Rate of
Intrauterine Growth of Infants of Low Birth Weight to Mortality, Morbidity,
and Congenital Anomalies," Journal of Pediatrics 69:531-545, October 1966.
204. Verghese, P.K.; Scott, R.B. ; Teixeira, G . ; and Ferguson, A.D., "Studies in
Growth and Development. XII Physical Growth of North American Negro
Children," Pediatrics 44: August 1969.
205. Vital Statistics of New York State, State Department of Health, 1973.
206. Washington, J.L., Brown, A., and Starrett , A., "Neonatal Mortality Among
Low Birth Weight Infants," The Journal of the Louisiana State Medical
Society 122:48-52, February 1970.
207. Wegman, M.E., "Annual Summary of Vital Statistics - 1973," Pediatrics 54,
December 1974.
208. Wegman, M.E., "Annual Summary of Vital Statistics - 1970," Pediatrics 48,
December 1971.
209. Wegman, M.E., "Annual Summary of Vital Statistics - 1967," Pediatrics,
p. 1005, 1968.
210. Wegman, M.E., "Annual Summary of Vital Statistics - 1956," Pediatrics 40,
1967.
211. Wegman, M.E., "Annual Summary of Vital Statistics - 1965," Pediatrics 38,
December 1956.
212. Wennberg, R.P., Schwartz, R. , and Sweet, A.Y. , "Early Versus Delayed
Feeding of Low Birth Weight Infants: Effects on Physiologic Jaundice,"
The Journal of Pediatrics 68:850-5, June 1965.
213. Wilkerson, L.R., Donnelly, J.F., and Abernathy, J.A. , "Perinatal Mortality
and Premature Births Among Pregnancies Complicated by Threatened Abortion,"
American Journal of Obstetrics and Gynecology : September 1, 1966.
214. Willocks, J., "The Study of Fetal Growth by Serial Cephalometry and Estriol
Measurements," Journal of Reproductive Medicine 6:189-193, April 1971.
BIBLIOGRAPHY (Continued)
215. Wood, C; Newman, W. ; Luitiley, J.; and Hammond, J., "Classification of Fetal
Heart Rate in Relation to Fetal Scalp Measurements and Apgar Score,"
American Journal of Obstetrics and Gynecology 105: November 1969.
216. Wright, et al., "A Controlled Follow-Up Study of Small Prematures Born
From 1952-1965," American Journal of Diseases of Children 124: October 1972.
217. Wu, P.Y.K. ; Teilmann, P.; Gabler, M. ; Vaughan , M. ; and Metcoff, J., "Early
Versus 'Late' Feeding of Low Birth Weight Neonates: Effect on Serum
Bilirubin, Blood Sugar, and Responses to Glucagon and Epinephrine
Tolerance Tests," Pediatrics 39:733-39, May 1967.
218. Yeh, Sze-Ya; Forsythe, A.; and Hon, E.H., "Quantification of Fetal Heart
Beat-to-Beat Interval Difference," Obstetrics and Gynecology 41: March 1973.
219. Yerushalmy, J., "The Classification of Newborn Infants by Birth Weight and
Gestational Age," Journal of Pediatrics : August 1957.
220. Zachman, R.D. ; Steinmetz, G.P.; Botham, R.J.; Graven, S.N.; and
Ledbetter, M.K. , "Incidence and Treatment of the Patent Ductus Arteriousus
in the 111 Premature Neonate," American Heart Journal 87:697-703, 1974.
221. Zachman, R.D., and Graven, S.N., "A Neonatal Intensive Care Unit," American
Journal of Diseases of Children 128: August 1974.
APPENDIX A
Birth Weight (gm): < 500 550 600 650 700 750 800 850 900 950 1000
Number of Live Births: (61) (33) (58) (56) (71) (69) (71) (79) (86) (132) (114)
*Data compiled from nine institutions
Figure 1. Number of Neonatal Survivors by Birth Weight during Years 1963-1974*
yyy2)i '^'J^ntisr of patients
Number of survivors
Birth Weight (gm): 500 550 600 650 700 750 800 850 900 950 1000
Survival (%): 0 3 3 2 4 6 7 15 19 - 21 37
*Data compiled from nine institutions
Figure 2. Total Number of Survivors by Birth Weight as a Fraction of the Total Number of Live Births*
12-49
0
Birth Weight (gm): < 500 550 600 650 700 750 800 850 900 950 1000
Numberof Live Births: (19) (15) (18) (25) (25) (34) (34) (44) (44) (62) (66)
(9) (6) (15) (11) (15) (7) (9) (17) (16) (29) (17)
•Data
Figure 3. Comparison of Number of Survivors by Birth Weight during Years
1963-1969 and 1970-1971*
Gestational Age (wks): < 24
Number of Live Births; (31)
24
25
26
27
28
29
30
31
32
33
58)
(43)
(82)
(54)
(67)
(50)
(63)
(71)
(72)
•Royal Victoria Hospital, University of Colorado, Uniuerslty of California at San Francisco
Figure 4. Neonatal Survival Rate by Gestational Age, 1964-1974*
E
I 30
I I Number of ;
Wa
Gestational Age (wks):
Survival (%):
25
26
27
28
29
30
31
32
6.8
15.8
42.5
46.2
64.0
71.4
85.9
90.2
<24
Figure 5. Neonatal Survival Rate by Gestational Age, 1964-1974
<24 24
25 26 27 28 29
Gestational Age (wks)
* Royal Victoria hHospitai, Montreal
University of Colorado, Denver
University of CalKornia, San Franci
Figure 6. Neonatal Survival Rate by Gestational Age, 1964-1974*
12-51
550 600 650 700
750 800 850
Birth Weight (gm)
900 950 1000 1050
.^_i
Royal Victoria Hospital
1966-74
22 23
24 25 26
Gestational Age (wks)
Figure 7. Survival Rates at the Borderline of Viability
12-52
1954-1962 1963-1967 1968-1971
Total
Deliveries*
33,736
22,260
16,057
3,339
3,089
Average
Deliveries/Yr.*
4,217
4,442
4,014
3,339
3,089
Still Births*
10.5/M
11.6/M
10.8/M
10.2/M
12.6/M
Neonatal
Deaths*
12.9/M
10.7/M
10.7/M
9.3/M
6.8/M
Perinatal
Mortality*
23.3/M
22.3/M
21.5/M
19.5/M
19.4/M
Monitoring
Acid-Base 0%
Heart Rate 0%
Acid-Base 5%
Heart Rate 0%
Acid- Base 10%
Heart Rate 5%
Acid-Base 10%
Heart Rate 10%
Acid-Base 25%
Heart Rate 52%
Figure 8. General Statistics — Presbyterian Hospital
:: 40 —
IQ Meant 15D
1965-66 67-68
69-70
Year
p
90 »
Figure 9. Infants Born at the University of California at San Francisco 1965-1974
Birth Weight 750-1500 Grams
12-53
5 15
1965
70
71
68 69
Year
Figure 10. Neonatal Mortality for University of California at San Francisco, City of San Francisco,
and the United States
28 30 32
Gestation (wks)
I Campbell, J. Obstet. Gynaec. Brit. Cwlth. 76:603. 1969.
Figure 11. Mean fetal biparietal diameter values + or - 2 standard deviations for each week
of gestation during the second half of normal pregnancy in 186 patients whose
gestation was known (471 individual measurements)
12-54
Period 1*
1960
Period 2
September-December
1972
Period 3
1973
Number of
Deliveries
566
1135
3092
1 Minute
Apgar <6
24.6%
13.1%
12.3%
5 Minute
Apgar <6
4.5%
3.3%
3.4%
Monitoring
Acid-Base 0%
Heart Rate 0%
Acid-Base 13%
Heart Rate 25%
Acid-Base 35%
Heart Rate 52%
nblned data Irom 12
Figure 12. Apgar Scores at 1 & 5 Minutes
a. 25
S! 5
C £
u ^ 15
V e
UJ 10
Unmonitored Cases = 181
Monitored Cases ° 213
Total Admissions - 394*
1-2
5-8
9-16
17 +
Days
*AII admissions with Qlrth Weight > 1000 gms Included.
Figure 13. Distribution of Length of Stay in Intensive Care Unit Presbyterian Hospital
September 1972-December 1973
12-55
Monitored Electronically
Unmonltored
Duration of Stay
Duration of Stay
8 Days or less
9 Days or more
8 Days or less
9 Days or more
80%
20%
60%
40%
Mean Duration of Stay
Mean Duration of Stay
6 Days
10 Days
Figure 14. Intensive Care Unit Recovery Time Requirements
Unlversily of California — San Fr,
Figure 15. Incidence of Respiratory Distress Syndrome per 1000 Live Births
With Birth Weight 750-2500 Grams, and Percent Survival Rate
> 2000 gms
Figure 16. Respiratory Distress Syndrome, Progressive IMeonatal Atelectasis Incidence
University of California at San Francisco
1964 65 66 67
70 71 72 73 74
Figure 17. Approximate Number of Improvements In Medical Technology
Approximate week of gestation when findings present
J Based on 300
s Single live births
[-all Caucasian
24
28
30
32
34
36
38
40
Head circumference
incmi 2SD
23-28.3
25-30.4
>o.8-
32.4
28.6-34
30.5-
35.5
32-36.5
33-37
<
i
Sole creases
Anterior transverse crease only
Occasional creases
Anterior two-thirds
Sole covered
1 If small may
< represent fetal
malnutrition
*
Breast nodule
diameter
Not paipable-absent
>-
2 mm
4 mm
7 mm
Scalp hair
Fine and fuzzy
Coarse a
nd silky
Hard to distinguish individual strands
Appear as ind
vidual strands
Ear lobe
Pliable -no cartilage
Some cartilage
Stiffened by
thick cartilage
Testes and
scrotum
Testes in lower canal
Scrotum small — few rugae
ntermediate
Testes pendulous, scrotum
full, extensive rugae
'
Benrman, R. E., Fisher, D., Paton, J. B., and Keller. J.: In utero disease and tne newborn Inlan
s In pediatrics, vol. 17, Chicago, Copyright © 1970 Dy Year Book Medical Publishers, used by i
i-Tlson, Brett, Koenlgsbergh, and Usher,)
(Adapted fron
Figure 18. Estimation of Gestational Age
AGE IN WEEKS 24
28
32
34
36 40
Traction
flexion of arms
always present
Grasp
finger grasp
fully developed
reflex
stronger
can be lifted off bed
Posture
frog-like p
limbs extended
and rolls
onto side
osition
limbs
extended
flexion of legs
stronger
flexion of
legs
flexion of all limbs
Neck righting
trunk follows
rotation of head
Tone: Recoil
hypotonic
hypotonic
slow recoil
in legs
good recoil
in arms
slow recoil
in arms
good recoil
in arms
Head
Lag
pendular
head
some attempt
to flex head
still lags
but less
initial lag
then sudden
flex
good tone
with head
righting
Ventral
Susp,
floppy
floppy
some flexion
of legs
increased flexio
arms
n of legs &
good flexion
of legs &
arms
Moro
complete
but easily
exhausted
complete
Pupil React.
present at
29 weeks
Glabella Tap
Suck
blink
strong
present but wea
<
synchronized
with swallowinc
Head turning
to light
Walking
present
slow on toes
feeble
easier
easier easy on heel
Figure 19. Neurologic Development Related to Gestational Age
APPENDIX B
Table 1. Variation in Gestational Ages at Different Weights*
Birth Weight in Grams
Estimated Weeks of Gestation
Under 500
22-28
501-750
22-30
751-1000
23-32
1001-1250
26-34
1251-1500
26-35
1501-1750
28-36
1751-2000
28-37
2001-2250
29-37
2251-2500
■ , 30-40
2501-2750
32-
2751-3000
33-
3001-3250
34-
3251-3500
Table 2. Variation in Weight at
Different Gestational Ages*
Estimated Weel<s
of Gestation
Recorded
Birth Weights
in Grams
22
460-600
23
550-950
24
500-850
25
600-1000
26
400-925
27
630-1050
28
680-1000
Table 3. Neonatal Survival Rate in New York City by
Weight at Birth and Race - 1962-1971
Birth Weight
(gm)
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
Under 1000
12.5
12.9
11.6
12.1
13.6
15.1
17.5
14.0
20.0
21.0
White
8.5
11.6
6.7
8.2
9.9
11.4
11.7
5.0
18.7
12.7
Nonwhite
16.4
14.2
16.1
15.5
16.7
17.9
22.6
21.2
21.2
28.2
1001-1500
55.0
55.7
56.2
59.2
63.4
64.1
65.5
61.0
66.6
66.2
White
49.5
50.2
47.4
52.0
59.1
56.8
61.1
52.5
61.6
57.2
Nonwhite
61.7
62.1
65.8
66.7
68.2
71.4
70.5
70.1
71.5
75.2
1501-2000
85.6
87.9
87.1
88.5
89.0
89.0
88.8
89.2
90.0
90.8
White
82.6
85.3
84.0
86.0
86.9
86.6
86.8
87.2
86.9
87.1
Nonwhite
90.1
91.4
91.1
91.6
91.8
92.3
91.6
91.6
93.7
94.2
2001-2500
96.8
97.2
97.2
97.4
97.6
97.8
97.7
97.4
97.7
97.5
White
96.5
96.8
96.9
96.9
97.2
97.5
97.1
97.1
97.3
96.8
Nonwhite
97.4
98.0
97.7
98.1
98.2
98.4
98.7
97.9
98.3
98.4
Under 2501
85.2
86.0
85.4
86.1
87.2
87.2
87.5
86.7
88.5
89.1
White
85.7
86.4
85.5
86.6
87.7
87.9
87.6
86.7
88.5
88.2
Nonwhite
84.3
85.4
85.1
85.3
86.5
86.2
87.3
86.7
88.4
90.2
12-59
Table 4. City of New York Permature Center Statistics Survival Percentages (by Weight) 1963
Total All Centers
White J
Weight Group
Born In
No. Survived
% Survival
Born Out
No. Survived
% Survival
Under 500 gms.
30
0
0
1
0
0
501-750 gms.
44
5
11.4
19
1
5.3
751-1000 gms.
82
22
26.8
43
20
46.5
1001-1250 gms.
81
42
51.8
90
49
54.4
1251-1500 gms.
123
80
65
158
125
79.1
1501-1750 gms.
173
139
80.3
193
174
91.1
1751-2000 gms.
284
256
90.1
236
222
94,1
2001-2500 gms.
1479
1443
97.5
96
85
88.5
TOTALS
2296
1986
86.5
836
676
80.9
Nonwhite
Under 500 gms.
98
0
0
3
0
0
501-750 gms.
98
3
3.1
20
1
5
751-1000 gms.
127
29
22.8
38
22
57.9
1001-1250 gms.
142
75
52.8
80
54
67.5
1251-1500 gms.
174
140
80.5
116
96
82.8
1501-1750 gms.
283
253
89.4
153
139
90.8
1751-2000 gms.
441
423
95.9
200
192
96
2001-2500 gms.
1795
1339
99.1
97
93
95.9
TOTALS
3158
2702
85.6
707
597
84.4
White and Nonwhite
Under 500 gms.
128
0
0
5
0
0
501-750 gms.
142
8
5.6
38
2
5.3
751-1000 gms.
209
51
24.4
81
42
51.8
1001-1250 gms.
223
117
52.5
170
103
60.6
1251-1500 gms.
297
220
74.1
274
221
80.6
1501-1 750 gms.
456
392
86
346
313
90.5
1751-2000 gms.
725
679
93.6
436
414
95
2001-2500 gms.
3274
3222
98.4
193
178
92.2
TOTALS
5454
4689
86
1543
1273
82.5
Survival Rate (Under 500 grams)
Hospital
White
Nonwhite
Su
vival
Survival
Survival
Survival
Born In
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
1
0
0
_
_
_
1
0
0
-
-
-
Bellevue
_
-
-
-
-
-
2
0
0
-
-
-
Bronx
7
0
0
—
—
—
3
0
0
-
—
Elmhurst
1
0
0
-
-
-
8
0
0
-
-
Flushing
_
-
-
—
-
-
_
-
_
—
—
Harlem
1
0
0
-
-
-
15
0
0
-
-
Jewish Brooklyn
_
_
—
-
—
—
_
-
—
—
—
Kings County
4
0
0
1
0
0
54
0
0
2
0
0
Lincoln
4
0
0
-
-
-
4
0
0
1
0
0
L. 1. Jewish
1
0
0
-
—
—
_
—
—
—
-
-
Mt. Sinai
5
0
0
-
-
-
1
0
0
-
-
-
New York
2
0
0
-
-
-
2
0
0
-
-
-
Queens Gen.
_
_
—
—
—
—
6
0
0
-
-
—
St. Vincent's (NY)
1
0
0
-
-
-
_
-
-
-
-
-
St. Vincent's (SI)
TOTALS
3
15
0
"o
0
i"
~0
-
2
98
0
~0
0
3
""o
-
0
0
0
0
12-60
Table 4 (Continued)
Survival Rate (501 -750 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
5
0
0
2
1
50
5
0
0
_
_
-
Bellevue
4
0
0
2
0
0
1
0
0
-
-
-
Bronx
4
0
0
-
-
-
5
1
20
-
-
-
Elmhurst
4
0
0
1
0
0
6
0
0
-
-
-
Flushing
-
-
-
1
0
0
-
-
-
1
0
0
Harlem
2
0
0
-
-
-
17
1
5.9
-
-
-
Jewish Brooklyn
-
-
-
3
0
0
2
0
0
3
0
0
Kings County
2
0
0
2
0
0
47
0
0
7
0
0
Lincoln
7
5
70.3
_
-
-
6
1
16.7
-
-
-
L. 1. Jewish
1
0
0
2
0
0
-
-
-
-
-
-
Mt. Sinai
7
0
0
4
0
0
2
0
0
4
0
0
New York
3
0
0
2
0
0
1
0
0
2
1
50
Queens Gen.
1
0
0
_
_
_
4
0
0
2
0
0
St. Vincent's (NY)
_
_
_
_
_
_
_
_
_
_
_
-
St. Vincent's (SI)
TOTALS
4
44
0
5
0
19
1
-
2
98
0
3
0
1
20
0
1
0
11.4
5.3
3.1
5.0
Survival Rate (751-1000 grams)
Hospital
White
Nonwhite
Born In
Survival
Born Out
Survival
Born In
Survival
Born Out
Survival
No.
%
No.
%
No.
%
No.
%
Babies
Bellevue
Bronx
Elmhurst
Flushing
Harlem
Jewish Brooklyn
Kings County
Lincoln
L. 1. Jewish
Mt. Sinai
New York
Queens Gen.
St. Vincent's (NY)
St. Vincent's (SI)
TOTALS
11
7
7
5
10
4
5
9
2
2
8
2
9
1
82
1
1
4
0
2
1
1
8
0
0
1
1
2
0
18
9.1
14.3
57.1
0
20
25
20
88.9
0
0
12.5
50
22.2
0
10
4
1
3
2
5
1
3
5
6
2
1
43
2
1
1
1
0
2
0
3
1
5
2
0
20
20
26
100
33.3
0
40
0
100
20
83.3
100
0
7
5
9
5
26
5
40
9
2
1
16
1
1
127
0
1
2
0
3
2
8
5
1
1
6
0
0
29
0
20
22.2
0
11.5
40
20
56.6
50
100
37.5
0
0
4
2
2
3
2
2
5
1
1
2
4
1
6
3
38
2
1
1
2
0
1
2
0
1
1
4
1
4
2
22
50
50
50
66.7
0
50
40
0
50
100
100
66.7
66.7
26.8
46.5
22.8
57.8
12-61
Table 4 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Born In
Survival
Born Out
Survival
Born In
Survival
Born Out
Survival
No.
%
No.
%
No.
%
No.
%
Babies
Bellevue
Bronx
Elmhurst
Flushing
Harlem
Jewish Brooklyn
Kings County
Lincoln
L. 1. Jewish
Mt. Sinai
New York
Queens Gen.
St. Vincent's (NY)
St. Vincent's (SI)
TOTALS
10
7
2
2
1
4
4
15
4
8
10
3
8
3
81
6
4
0
1
0
3
2
7
2
6
6
1
2
2
42
60
57.1
0
50
0
75
50
46.7
50
75
60
33.3
25
66.7
8
5
3
9
4
5
12
4
14
9
6
8
3
90
5
3
1
4
0
1
8
0
10
3
5
6
3
49
62.5
60
33.3
44.4
0
20
66.7
0
71.4
33.3
83.3
75
100
8
2
6
4
1
35
7
44
19
1
2
13
142
6
2
3
0
1
19
5
23
10
0
1
5
75
75
100
50
0
100
54.3
71.4
52.3
52.6
0
50
38.5
n
3
4
8
7
7
10
5
6
4
5
10
80
5
2
4
6
4
4
7
5
4
3
3
7
54
45.5
66.7
100
75
57.1
57.1
70
100
66.7
75
60
70
51.8
54.4
52.8
67.5
Survival Rate (125
-1500
grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
rj 1
No.
%
No.
%
No.
%
No.
%
Babies
7
3
42.9
11
7
63.6
8
7
87.5
9
8
88.9
Bellevue
10
3
30
8
6
75
6
5
83.3
6
6
100
Bronx
11
8
72.7
9
8
88.9
2
2
100
4
3
75
Elmhurst
9
7
77.8
10
8
80
3
1
33.3
5
4
80
Flushing
9
6
66.7
16
13
81.2
2
2
100
4
3
75
Harlem
-
-
-
5
5
100
24
21
87.5
2
2
100
Jewish Brooklyn
6
4
66.7
19
17
89.5
8
7
87.5
19
18
94.7
Kings County
5
3
60
3
2
66.7
62
46
74.2
6
3
50
Lincoln
17
15
88.2
1
1
100
28
26
92.8
2
2
100
L. 1. Jewish
5
3
60
24
19
79.2
-
-
-
8
7
87.5
Mt. Sinai
20
12
60
15
12
80
4
3
75
9
8
88.9
New York
12
8
66.7
7
4
57.1
7
5
71.4
7
7
100
Queens Gen.
2
2
100
6
5
83.3
19
14
73.7
5
4
80
St. Vincent's (NY)
7
5
71.4
16
11
68.7
_
-
_
17
11
64.7
St. Vincent's (SI)
TOTALS
3
123
1
80
33.1
8
158
7
125
87.5
1
174
1
140
100
13
116
10
96
76.9
65.0
79.1
80.5
82.8
Table 5. City of New York Premature Center Statistics Survival Percentages (by Weight) 1964
Total All Centers
White I
Weight Group
Born In
No. Survived
% Survival
Born Out
No. Survived
% Survival
Under 500 gms.
35
0
0
2
0
0
501-750 gms.
56
9
16.1
8
1
12,5
751-1000 gms.
73
14
19.2
43
16
37.2
1001-1250 gms.
89
39
43.8
82
58
70.7
1251-1500 gms.
121
87
71.9
144
116
80.6
1501-1750 gms.
189
157
83.1
227
200
88.1
1751-2000 gms.
317
287
90.5
245
221
90.2
2001-2500 gms.
1325
1281
96.7
68
63
92.6
TOTALS
2'205
1874
85
819
675
82.4
Nonwhite
Under 500 gms.
144
0
0
5
0
0
501-750 gms.
118
8
6.8
22
3
3.6
751-1000 gms.
129
37
28.7
37
16
43.2
1001-1250 gms.
131
71
54.2
79
56
70.9
1251-1500 gms.
224
170
75.9
124
114
91.9
1501-1 750 gms.
286
248
86.7
175
166
94.9
1751-2000 gms.
433
409
94.5
166
162
97.6
2001-2500 gms.
1721
1701
98.8
104
97
93.3
TOTALS
3186
2644
83
711
614
86.2
White and Nonwhite
Under 500 gms.
179
0
0
7
0
0
501-750 gms.
174
17
9.8
29
3
10.3
751-1000 gms.
202
51
25.2
80
32
40
1001-1250 gms.
220
110
50
161
114
70.8
1251-1500 gms.
345
257
74.5
268
230
85.8
1501-1750 gms.
475
405
85.3
402
366
91
1751-2000 gms.
750
696
92.8
411
383
93.2
2001-2500 gms.
3046
2982
97.9
172
160
93
TOTALS
5391
4518
83.8
1530
1288
84.2
Survival Rate (Under 500 grams)
Hospital
White
Nonwhite
Su
vival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
2
0
0
_
-
-
1
0
0
-
-
-
Bellevue
4
0
0
-
-
-
1
0
0
-
-
-
Bronx
6
0
0
—
-
—
12
0
0
-
-
—
Elmhurst
4
0
0
-
-
-
3
0
0
-
-
-
Flushing
—
—
—
—
—
—
—
—
_
—
—
—
Harlem
-
-
-
-
-
-
26
0
0
-
-
-
Jewish Brooklyn
-
-
-
-
-
-
_
-
-
-
-
-
Kings County
2
0
0
-
-
-
78
0
0
4
0
0
Lincoln
12
0
0
—
—
—
14
0
0
—
-
-
L. 1. Jewish
-
-
-
-
-
-
-
-
-
-
Mt. Sinai
—
—
—
—
1
0
0
-
-
—
New York
1
0
0
-
_
-
1
0
0
-
-
Queens Gen.
1
0
0
_
—
—
5
0
0
1
0
0
St. Vincent's (NY)
3
0
0
1
0
0
_
_
_
-
-
-
St. Vincent's (SI)
TOTALS
35
~0
-
1
2
0
"~0
0
2
144
0
0
~5
~
-
0
0
0
0
Table 5 (Continued)
Survival Rate (501-750 grams)
Hospital
White
Non
white
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
1
0
0
1
0
0
7
1
14,3
2
0
0
Bellevue
5
0
0
1
1
100
4
0
0
3
0
0
Bronx
7
0
0
-
-
-
6
0
0
-
-
-
Elmiiurst
1
0
0
-
-
-
1
0
0
1
0
0
Flushing
3
0
0
-
-
-
-
-
-
-
-
-
Harlem
-
-
-
-
-
-
25
0
0
-
-
-
Jewish Brooklyn
4
1
25
2
0
0
3
0
0
2
0
0
Kings County
2
0
0
-
-
-
47
0
0
2
0
0
Lincoln
17
8
47.1
-
-
-
11
6
54.5
2
1
50
L. 1. Jewish
2
0
0
-
-
-
-
-
-
2
0
0
Mt. Sinai
1
0
0
1
0
0
1
0
0
-
-
-
New York
8
0
0
2
0
0
3
0
0
2
0
0
Queens Gen.
2
0
0
-
_
-
9
1
11.1
4
0
0
St. Vincent's (NY)
1
0
0
1
0
0
-
-
-
1
1
100
St. Vincent's (SI)
TOTALS
2
56
0
9
0
16.1
8
1
-
1
118
0
8
0
21
2
-
12.5
6.8
9.5
Survival Rate (751-1000 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
9
1
11.1
6
3
50
6
1
16.7
3
1
33.3
Bellevue
9
3
33.4
3
0
0
2
0
0
1
0
0
Bronx
9
0
0
-
-
-
12
3
25
1
0
0
Elmhurst
4
0
0
3
0
0
6
0
0
5
2
40
Flushing
5
1
20
5
3
60
1
1
100
1
0
0
Harlem
-
-
-
-
-
-
24
7
29.2
4
3
75
Jewish Brooklyn
4
1
25
4
4
100
6
4
66.7
2
1
50
Kings County
-
-
-
-
-
-
38
8
21.1
3
1
33.3
Lincoln
8
4
50
-
-
-
10
7
70
2
2
100
L. 1. Jewish
-
-
-
7
1
14.3
_
_
-
3
2
66.7
Mt. Sinai
13
2
15.4
2
1
50
4
2
50
2
1
50
New York
4
2
50
5
0
0
2
0
0
1
0
0
Queens Gen.
1
0
0
1
0
0
12
2
16.7
2
0
0
St. Vincent's (NY)
3
0
0
6
4
67
4
2
50
4
1
25
St. Vincent's (SI)
TOTALS
4
73
0
14
0
19.2
1
43
0
16
0
2
129
0
37
0
3
37
2
16
66.7
37.2
28.7
43.2
12-64
Table 5 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Born in
Survival
Born Out
Survival
Born In
Survival
Born Out
Survival
No.
%
No.
%
No.
%
No.
%
Babies
Bellevue
Bronx
Elmhurst
Flushing
Harlem
Jewish Brooklyn
Kings County
Lincoln
L. 1. Jewish
Mt. Sinai
New York
Queens Gen.
St. Vincent's (NY)
St. Vincent's (SI)
TOTALS
11
12
7
8
3
3
3
10
3
7
11
3
3
5
89
3
5
5
3
0
2
2
7
2
4
2
1
1
2
39
27.3
41.7
71.4
37.5
0
66.7
66.7
70
66.7
57.1
18.2
33.3
33.3
40
11
1
1
7
3
1
9
1
16
2
9
8
6
7
82
8
0
1
6
1
1
5
0
9
1
8
6
6
6
58
72.7
0
100
85.7
33.3
100
56.6
0
56.2
50
88.9
75
100
85.7
5
4
10
7
28
10
37
13
2
3
10
1
1
131
2
2
2
3
17
9
18
10
1
3
4
0
0
71
40
50
20
42.9
60.7
90
48.6
77
50
100
40
0
0
6
1
1
3
2
6
8
8
3
11
8
4
3
5
10
79
5
1
0
2
2
5
6
2
3
9
5
2
2
5
7
56
83.3
100
0
66.7
100
83.3
75
25
100
81.8
62.5
50
66.7
100
70
43.8
70.7
54.2
70.9
Survival Rate (1251-1500
grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
5
1
20
11
8
72.7
8
5
62.5
8
8
100
Bellevue
17
10
58.8
6
4
66.7
8
5
62.5
4
3
75
Bronx
11
8
72.7
4
4
100
18
15
83.3
-
-
-
Elmhurst
12
10
83.3
4
3
75
11
8
72.7
8
8
100
Flushing
11
8
72.7
14
11
78.6
2
2
100
7
7
100
Harlem
-
-
-
3
3
100
42
29
69
3
3
100
Jewish Brooklyn
8
8
100
23
16
69.6
15
10
66.7
15
14
93.3
Kings County
2
2
100
-
-
-
66
50
75.8
2
1
50
Lincoln
8
7
87.5
2
2
100
16
14
87.5
6
6
100
L. 1. Jewish
6
3
50
18
15
83.3
-
-
-
13
9
69.2
Wit. Sinai
13
10
77
12
9
75
5
3
60
13
12
92.3
New York
9
5
55.6
12
9
75
4
4
100
11
11
100
Queens Gen.
4
3
75
8
7
87.5
26
23
88.5
9
9
100
St. Vincent's (NY)
9
7
77.8
18
17
94.4
2
1
50
10
9
90
St. Vincent's (SI)
TOTALS
6
121
5
87
83.3
9
144
8
116
88.9
1
224
1
170
100
15
124
14
114
93.3
71.9
80.6
75.9
91.9
12-65
Table 6. City of New York Premature Center Statistics Survival Percentages (by Weight) 1965
Total All Centers
White 1
Weight Group
Born In
No. Survived
% Survival
Born Out
No. Survived
% Survival
Under 500 gms.
16
0
0
2
0
0
501-750 gms.
53
0
0
12
0
0
751-1000 gms.
83
18
21.7
48
21
43.7
1001-1250 gms.
84
45
53.6
75
49
65.3
1251-1500 gms.
89
54
60.7
134
102
76.1
1501-1 750 gms.
184
144
78.3
195
172
88.2
1751-2000 gms.
247
227
91.9
203
192
94.6
2001-2500 gms.
1503
1473
98
85
75
88.2
TOTALS
2259
1961
86.8
754
611
81
IMonwhite |
Under 500 gms.
113
0
0
3
0
0
501-750 gms.
125
1
0.8
13
3
23.1
751-1000 gms.
123
35
28.5
44
20
45.5
1001-1 250 gms.
153
92
60.1
75
58
77.3
1251-1500 gms.
208
154
74.0
123
112
91.1
1501-1 750 gms.
281
250
89.0
155
149
96.1
1751-2000 gms.
349
334
95.7
166
161
97
2001-2500 gms.
1654
1638
99
92
91
98.9
TOTALS
3006
2504
83.3
671
594
88.5
White and Nonwhite
Under 500 gms.
129
0
0
5
0
0
501-750 gms.
178
1
0.6
25
3
12
751-1000 gms.
206
53
25.7
92
41
44.6
1001-1250 gms.
237
137
57.8
150
107
71.3
1251 -1500 gms.
297
208
70
257
214
83.3
1501-1 750 gms.
465
394
84.7
350
321
91.7
1751-2000 gms.
596
561
94.1
369
353
95.7
2001-2500 gms.
3157
3111
98.5
177
166
93.8
TOTALS
5265
4465
84.8
1425
1205
84.6
Survival Rate (Under 500 grams)
Hospital
White
Nonwhite
Born In
Su
vival
Born Out
Survival
Born In
Survival
Born Out
Survival
No.
%
No.
%
No.
%
No.
%
Babies
2
0
0
_
_
_
3
0
0
_
_
_
Bellevue
_
_
_
_
_
_
-
_
-
-
-
Bronx
3
0
0
_
-
-
2
0
0
-
-
-
Elmhurst
-
-
-
-
-
-
-
-
-
-
-
-
Flushing
—
—
—
—
—
—
—
—
—
—
—
Harlem
—
—
—
—
—
18
0
0
—
-
—
Jewish Brooklyn
-
-
-
-
-
-
3
0
0
-
-
-
Kings County
2
0
0
1
0
0
70
0
0
2
0
0
Lincoln
—
—
—
—
—
_
5
0
0
-
-
-
L. 1. Jewish
1
0
0
-
-
-
-
-
-
-
-
-
Mt. Sinai
1
0
0
—
—
—
—
—
—
—
—
—
New York
1
0
0
1
0
0
-
-
-
1
0
0
Queens Gen.
2
0
0
-
-
-
10
0
0
-
-
-
St. Vincent's (NY)
2
0
0
—
—
—
1
0
0
-
—
—
St. Vincent's (SI)
TOTALS
2
0
~0
0
~~2
"o
-
1
113
0
0
3
~
-
0
0
0
0
12-66
Tabte 6 (Continued)
Survival Rate (501-750 grams)
Hospital-
White
Nonwhite
Survival
Survival
Su
vival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
9
0
0
_
_
_
8
0
0
_
_
_
Bellevue
3
0
0
-
-
-
2
0
0
2
0
0
Bronx
6
0
0
-
-
-
7
0
0
-
-
-
Elmhurst
3
0
0
-
-
-
6
0
0
1
0
0
Flushing
-
-
-
-
-
-
-
-
-
1
0
0
Harlem
-
-
-
-
-
-
29
0
0
1
0
0
Jewish Brooklyn
2
0
0
3
0
0
6
0
0
-
-
-
Kings County
4
0
0
-
-
-
38
0
0
3
0
0
Lincoln
4
0
0
-
-
-
8
0
0
-
-
-
L. 1. Jewish
2
0
0
1
0
0
-
-
-
1
0
0
Mt. Sinai
7
0
0
-
-
-
2
0
0
1
0
0
New York
7
0
0
1
0
0
2
0
0
2
2
100
Queens Gen.
1
0
0
3
0
0
15
1
6.7
1
1
100
St. Vincent's (NY)
3
0
0
2
0
0
2
0
0
-
-
-
St. Vincent's (SI)
2
0
0
2
0
0
-
-
-
-
-
-
TOTALS
53
0
0
12
0
0
125
1
0.8
13
3
23.1
Survival Rate (751-1000 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
D r\ *
No.
%
No.
%
No.
%
No.
%
Babies
13
1
7.7
7
2
28.6
7
1
14.3
2
1
50
Bellevue
7
1
14.3
3
1
33.3
3
1
33.3
2
0
0
Bronx
14
1
7.1
1
0
0
6
0
0
2
1
50
Elmhurst
5
0
0
1
1
100
10
4
40
2
1
50
Flushing
5
2
40
6
3
50
-
-
-
4
3
75
Harlem
-
-
-
-
-
-
30
9
30
3
0
0
Jewish Brooklyn
3
2
66.7
5
2
40
8
3
37.5
4
2
50
Kings County
-
-
-
-
-
-
35
9
25.7
5
1
20
Lincoln
6
2
33.3
1
1
100
4
1
25
3
2
66.7
L. 1. Jewish
4
2
50
9
6
66.7
-
-
-
6
4
66.7
Mt. Sinai
5
2
40
4
1
25
-
-
-
3
2
66.7
New York
7
1
14.3
6
2
33.3
1
1
100
4
1
25
Queens Gen.
5
2
40
1
1
100
18
6
33.3
1
1
100
St. Vincent's (NY)
5
1
20
2
0
0
-
-
-
1
0
0
St. Vincent's (SI)
4
1
25
2
1
50
1
0
0
2
1
50
TOTALS
83
18
21.7
48
21
43.7
123
35
28.5
44
20
45.5
12-67
Table 6 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Survival
Survival
Su
viva!
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
9
4
44.4
9
3
33.3
8
5
62.5
6
6
100
Bellevue
7
3
42.9
3
2
66.7
6
3
50
3
3
100
Bronx
7
0
0
-
-
-
12
7
58.3
4
3
75
Elmhurst
4
4
100
4
2
50
3
0
0
3
1
33.3
Flushing
6
4
66.7
2
0
0
-
-
-
-
Harlem
-
-
-
-
-
-
28
23
82.1
6
4
66.7
Jewish Brooklyn
10
9
90
7
3
42.9
23
11
47.8
10
8
80
Kings County
4
2
50
-
-
-
34
20
58.8
4
3
75
Lincoln
1
1
100
3
2
66.7
9
7
77.8
_
_
_
L. 1. Jewish
4
4
100
21
13
61.9
-
-
-
12
8
66.7
Mt. Sinai
11
3
27.3
11
10
90.9
2
2
100
5
4
80
New York
11
7
63.6
6
5
83.3
3
2
66.7
5
5
100
Queens Gen.
3
2
66.7
2
2
100
23
12
52.2
3
?
66.7
St. Vincent's (NY)
5
2
40
3
3
100
_
_
5
4
80
St. Vincent's (SI)
TOTALS
2
84
0
45
0
4
75
4
49
100
2
153
0
92
0
9
75
7
58
77.8
53.6
65.3
60.1
77.3
Survival Rate (1251-1500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
8
3
37.5
9
5
55.6
9
5
55.6
8
8
100
Bellevue
8
4
50
7
5
71.4
4
2
50
8
6
75
Bronx
4
1
25
6
5
83.3
13
10
76.9
6
5
83.3
Elmhurst
6
6
100
14
13
92.9
9
4
44.4
3
3
100
Flushing
11
8
72.7
4
2
50
5
2
40
6
5
83.3
Harlem
-
-
-
2
2
100
36
30
83.3
9
8
88.9
Jewish Brooklyn
2
2
100
10
7
70
18
13
72.2
9
8
88.9
Kings County
5
0
0
2
0
0
69
52
75.4
8
7
87.5
Lincoln
9
4
44.4
1
1
100
16
13
81.2
2
2
100
L. 1. Jewish
3
3
100
20
15
75
-
-
-
18
17
94.4
Mt. Sinai
9
7
77.8
20
16
80
6
6
100
8
6
75
New York
11
7
63.6
8
7
87.5
3
3
100
4
4
100
Queens Gen.
2
0
0
6
6
100
19
13
68.4
10
9
90
St. Vincent's (NY)
9
7
77.8
12
9
75
-
-
-
8
8
100
St. Vincent's (SI)
TOTALS
2
89
2
54
100
13
134
9
102
69.2
1
208
1
154
100
16
123
16
112
100
60.7
76.1
74
91.1
12-68
Table 7. City of New York Premature Center Statistics Survival Percentages (by Weight) 1967
Total All Centers
White
Weight Group
Born In
No. Survived
% Survival
Born Out
No. Survived
% Survival
Under 500 gnw.
19
0
0
3
0
0
501-750 gms.
36
0
0
14
4
28.6
751-1000 gms.
58
12
20.7
35
19
54.3
1001-1250 gms.
83
47
76.6
73
51
69.9
1251-1500 gms.
127
77
60.6
103
85
82.5
1501-1750 gms.
162
130
80.2
160
142
83.7
1751-2000 gms.
235
214
91.1
221
208
94.1
2001-2500 gms.
1398
1358
97.1
91
83
91.2
TOTALS
2118
1838
86.8
700
592
84.6
Nonwfhite |
Under 500 gms.
100
0
0
1
0
0
501-750 gms.
107
3
2.8
11
2
18.2
751-1000 gms.
108
19
17.6
32
18
56.2
1001-1 250 gms.
129
71
55.0
83
63
75.9
1251-1 500 gms.
164
131
79.9
95
87
91.6
1501-1 750 gms.
236
219
92.8
142
136
95.8
1751-2000 gms.
331
314
94.9
154
147
95.5
2001-2500 gms.
1297
1281
98.8
55
51
92J
TOTALS
2472
2038
82.4
573
504
88
White and Nonwhite
Under 500 gms.
119
0
0
4
0
0
501-750 gms.
143
3
2.1
25
6
24
751-1000 gms.
166
31
18.7
67
37
55.2
1001-1250 gms.
212
118
55.7
156
114
73.1
1251-1500 gms.
291
208
71.5
198
172
86.9
1501-1750 gms.
398
349
87.7
302
278
92.1
1751-2000 gms.
566
528
93.3
375
355
94.7
2001-2500 gms.
2695
2639
97.9
146
134
91.8
TOTALS
4590
3876
84.4
1273
1096
86.1
Survival Rate (Under 500 grams)
Hospital
White
Nonwhite
Born In
Survival
Born Out
Survival
Born In
Survival
Born Out
Survival
No.
%
No.
%
No.
%
No.
%
Babies
-
-
-
-
-
-
4
0
0
-
_
_
Bellevue
3
0
0
—
-
—
1
0
0
-
-
—
Bronx
1
0
0
-
-
-
2
0
0
-
-
-
Brooklyn
1
0
0
-
-
-
4
0
0
-
-
-
Elmhurst
2
0
0
-
-
-
1
0
0
-
-
-
Flushing
—
—
—
—
—
—
—
—
—
—
—
—
Harlem
-
-
-
-
-
-
31
0
0
-
-
-
Jewish Brooklyn
Kings County
Lincoln
2
2
0
0
0
0
1
1
0
0
0
0
48
0
0
1
0
0
L. 1. Jewish
—
-
—
—
-
—
—
—
-
-
—
Mt. Sinai
1
0
0
-
-
-
1
0
0
-
-
-
New York
1
0
0
—
-
—
-
-
_
-
—
—
Queens Gen.
1
0
0
1
0
0
6
0
0
-
-
-
St. Vincent's (NY)
1
0
0
-
-
-
1
0
0
-
-
-
St. Vincent's (SI)
TOTALS
4
19
0
~0
0
3
~0
-
1
Too
0
~0
0
T
~0
-
0
0
0
0
12-69
Table 7 (Continued)
Survival Rate (501-750 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
6
0
0
1
0
0
5
0
0
_
_
_
Bellevue
5
0
0
2
1
50
1
0
0
-
-
_
Bronx
3
0
0
_
-
_
2
0
0
_
-
-
Brooklyn
3
0
0
-
_
_
6
0
0
3
1
33
Elmhurst
4
0
0
1
0
0
1
0
0
1
0
0
Flushing
-
-
-
-
_
_
_
_
-
_
-
_
Harlem
_
_
_
_
_
_
26
1
3.8
_
_
_
Jewish Brooklyn
-
_
_
_
_
_
4
1
25
_
_
_
Kings County
1
0
0
1
0
0
33
1
3
1
1
100
Lincoln
4
0
0
1
0
0
8
0
0
3
3
100
L. 1. Jewish
4
0
0
2
1
50
_
-
-
_
-
-
iVlt. Sinai
2
0
0
_
_
_
_
_
_
_
_
_
New York
1
0
0
-
_
_
3
0
0
_
-
-
Queens Gen.
-
-
-
2
1
50
17
0
0
1
0
0
St. Vincent's (NY)
1
0
0
2
1
50
1
0
0
2
1
50
St. Vincent's (SI)
2
0
0
2
0
0
-
-
-
-
-
-
TOTALS
36
0
0
14
4
28.6
107
3
2.8
11
2
18
Survival Rate (751-1000 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
6
1
16.7
_
_
_
3
1
33.3
_
_
_
Bellevue
4
0
0
4
1
25
3
0
0
-
-
-
Bronx
6
1
16.7
4
1
25
8
4
50
1
1
100
Brooklyn
1
0
0
2
2
100
2
0
0
7
3
42.9
Elmhurst
2
0
0
3
1
33.3
3
0
0
_
_
_
Flushing
1
0
0
1
1
100
1
0
0
_
_
_
Harlem
-
_
_
_
_
_
16
4
25
4
2
50
Jewish Brooklyn
3
1
33.3
2
1
50
7
2
28.6
2
0
0
Kings County
5
0
0
1
1
100
43
4
9.3
5
2
40
Lincoln
6
0
0
-
_
_
7
2
28.6
1
1
100
L. I.Jewish
3
2
66.7
3
1
33.3
-
-
-
4
3
75
IVlt. Sinai
16
5
31.2
5
3
60.0
1
1
100
1
1
100
New York
2
1
50
3
3
100
5
0
0
3
3
100
Queens Gen.
1
0
0
2
1
50
8
1
12.5
1
1
100
St. Vincent's (NY)
1
0
0
4
2
50
1
0
0
3
1
33.3
St. Vincent's (SI)
1
1
100
1
1
100
-
-
-
-
-
-
TOTALS
58
12
20.7
35
19
54.3
108
19
17.6
32
18
56.2
Table 7 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
P 1
D r\ ♦
No.
%
No.
%
No.
%
No.
%
Babies
7
5
71.4
1
1
100
9
4
44.4
5
3
60
Bellevue
7
4
57.1
5
2
40
1
0
0
2
2
100
Bronx
4
1
25
5
2
40
5
3
60
1
1
100
Brooklyn
3
0
0
2
2
100
1
0
0
12
8
66.7
Elmhurst
5
4
80
6
3
50
2
1
50
5
4
80
Flushing
5
3
60
6
3
50
-
-
-
1
1
100
Harlem
-
-
-
-
-
-
19
14
73.7
1
1
100
Jewish Brooklyn
3
3
100
5
4
80
18
9
50
9
8
88.9
Kings County
-
-
-
-
-
-
42
19
45.2
7
4
57.1
Lincoln
12
4
33.3
1
0
0
11
7
63.6
1
1
100
L. 1. Jewish
7
3
42.9
11
9
81.8
-
-
-
14
8
57.1
Mt. Sinai
6
3
50
6
4
66.7
5
4
80
6
6
100
New York
13
10
76.9
4
4
100
2
2
100
5
5
100
Queens Gen.
3
3
100
3
2
66.7
14
8
57.1
4
2
50
St. Vincent's (NY)
5
4
80
14
11
78.6
_
_
_
8
8
100
St. Vincent's (SI)
3
0
0
4
4
100
-
-
-
2
2
100
TOTALS
83
47
56.6
73
51
69.9
129
71
55
83
63
75.9
Survival Rate (1251
-1500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
11
7
63.6
2
2
100
9
9
100
5
4
80
Bellevue
12
7
58.3
7
4
57.1
2
1
50
6
5
83.3
Bronx
9
4
44.4
2
2
100
9
7
77.8
3
3
100
Brooklyn
4
2
50
10
9
90
3
3
100
18
18
100
Elmhurst
9
6
66.7
4
3
75
2
2
100
2
2
100
Flushing
10
5
50
4
2
50
-
-
-
2
2
100
Harlem
-
-
-
2
2
100
38
31
81.6
1
1
100
Jewish Brooklyn
8
6
75
5
5
100
22
18
81.8
3
3
100
Kings County
1
0
0
3
3
100
46
34
73.9
4
2
50
Lincoln
9
5
55.6
1
1
100
11
6
54.5
5
3
60
L. 1. Jewish
6
4
66.7
24
21
87.5
-
-
-
11
11
100
Mt. Sinai
22
18
81.8
6
6
100
5
5
100
4
4
100
New York
4
3
75
8
7
87.5
3
3
100
11
11
100
Queens Gen.
-
-
-
2
1
50
10
9
90
7
7
100
St. Vincent's (NY)
14
6
42.9
14
12
85.7
3
2
66.7
6
6
100
St. Vincent's (SI)
8
4
50
9
5
55.6
1
1
100
7
5
71.4
TOTALS
127
77
60.6
103
85
82.5
164
131
79.9
95
87
91.6
Table 8. City of New York Premature Center Statistics Survival Percentages (by Weight) 1968
Total All Centers
White 1
Weight Group
Born In
No. Survived
% Survival
Born Out
No. Survived
% Survival
Under 500 gms.
22
0
0
3
0
0
501-750 gms.
51
1
2
18
0
0
751-1000 gms.
76
18
23.7
37
19
51.4
1001-1250 gms.
70
34
48.6
64
47
73.4
1251-1500 gms.
104
75
72.1
135
117
86.7
1501-1750 gms.
159
134
84.3
208
185
88.9
1751-2000 gms.
245
228
93.1
261
247
94.6
2001-2500 gms.
1341
1304
97.2
100
90
90
TOTALS
2068
1794
86.8
826
705
85
Nonwhite
Under 500 gms.
87
0
0
1
0
0
501-750 gms.
100
8
8
13
0
0
751-1000 gms.
105
29
27.6
42
26
61.9
1001-1250 gms.
116
66
56.9
52
40
76.9
1251-1500 gms.
151
125
82.8
88
80
90.9
1501-1 750 gms.
222
189
85.1
128
119
93
1751-2000 gms.
323
312
96.6
178
174
97.8
2001-2500 gms.
1228
1218
99.2
88
85
96.6
TOTALS
2332
1947
83.5
590
524
88.8
White and Nonwhite
Under 500 gms.
109
0
0
4
0
0
501-750 gms.
151
9
6
31
0
0
751-1000 gms.
181
47
26
79
45
57
1001-1 250 gms.
186
100
53.8
116
87
75
1251-1500 gms.
255
200
78.4
223
197
88.3
1501-1750 gms.
381
323
84.8
336
304
90.5
1751-2000 gms.
568
540
95.1
439
421
95.9
2001-2500 gms.
2569
2522
98.2
188
175
93.1
TOTALS
4400
3741
85
1416
1229
86.8
Survival Rate (Under 500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
2
0
0
-
-
-
1
0
0
-
-
-
Bellevue
3
0
0
-
-
—
1
0
0
-
—
—
Bronx
3
0
0
-
-
-
2
0
0
-
-
-
Brooklyn
-
-
-
-
-
-
3
0
0
-
-
-
Elmhurst
1
0
0
—
—
—
1
0
0
—
—
—
Flushing
1
0
0
-
-
-
-
-
-
-
-
-
Harlem
2
0
0
—
—
—
17
0
0
-
-
—
Jewish Brooklyn
-
-
-
-
-
-
2
0
0
-
-
-
Kings County
1
0
0
-
-
-
53
0
0
-
-
-
Lincoln
3
0
0
1
0
0
-
-
-
-
-
-
L. 1. Jevi/ish
-
—
—
—
-
—
—
—
—
—
—
—
Mt. Sinai
5
0
0
1
0
0
—
—
—
-
—
—
New York
-
-
-
1
0
0
-
-
-
-
-
-
Queens Gen.
-
—
—
—
_
_
4
0
0
—
—
—
St. Vincent's (NY)
1
0
0
-
_
_
-
-
-
-
-
-
St. Vincent's (SI)
-
-
-
-
-
-
3
0
0
1
0
0
TOTALS
22
0
0
3
0
0
87
0
0
1
0
0
12-72
Table 8 (Continued)
Survival Rate (501-750 grams)
Hospital
■
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
6
0
0
2
0
0
6
1
16.7
_
_
_
Bellevue
5
0
0
-
-
-
1
0
0
1
0
0
Bronx
7
0
0
-
-
-
3
0
0
-
-
-
Brooklyn
3
0
0
2
0
0
3
0
0
1
0
0
Elmhurst
1
0
0
2
0
0
5
0
0
2
0
0
Flushing
-
-
-
-
-
-
-
-
-
1
0
0
Harlem
2
0
0
-
-
-
19
4
21.1
-
-
-
Jewish Brooklyn
2
1
50
-
-
-
7
2
28.6
-
-
-
Kings County
1
0
0
2
0
0
36
1
2.8
2
0
0
Lincoln
3
0
0
-
-
-
4
0
0
1
0
0
L. 1. Jewish
-
-
-
1
0
0
1
0
0
1
0
0
Mt. Sinai
3
0
0
3
0
0
1
0
0
-
-
-
New York
7
0
0
4
0
0
3
0
0
-
-
-
Queens Gen.
2
0
0
-
-
-
10
0
0
-
-
-
St. Vincent's (NY)
6
0
0
1
0
0
-
-
_
2
0
0
St. Vincent's (SI)
3
0
0
1
0
0
1
0
0
2
0
0
TOTALS
51
1
2
18
0
0
100
8
8
13
0
0
Survival Rate (751-1000 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
12
2
16.7
5
3
60
7
1
14.3
2
1
50
Bellevue
3
0
0
2
1
50
2
0
0
-
-
-
Bronx
8
2
25
1
1
100
5
4
80
-
-
-
Brooklyn
4
1
25
3
1
33.3
3
1
33.3
6
4
66.7
Elmhurst
1
0
0
1
1
100
3
2
66.7
1
0
0
Flushing
3
2
66.7
1
0
0
-
-
-
2
1
50
Harlem
1
0
0
1
0
0
13
2
15.4
1
1
100
Jewish Brooklyn
1
0
0
1
0
0
10
4
40
5
3
60
Kings County
2
0
0
5
2
40
43
9
20.9
6
2
33.3
Lincoln
5
0
0
-
-
-
2
2
100
-
-
-
L. 1. Jewish
5
2
40
5
4
80
-
-
-
4
3
75
Mt. Sinai
17
8
47.1
4
3
75
-
-
-
-
-
-
New York
5
0
0
3
1
33.3
5
3
60
4
2
50
Queens Gen.
2
0
0
-
-
-
9
0
0
3
1
33.3
St. Vincent's (NY)
3
0
0
5
2
40
2
1
50
8
8
100
St. Vincent's (SI)
4
1
25
-
-
-
1
0
0
-
-
-
TOTALS
76
18
23.7
37
19
51.4
105
29
27.6
42
26
61.9
12-73
Table 8 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
5
1
20
_
_
_
8
4
50
1
1
100
Bellevue
3
2
66.7
2
1
50
4
3
75
2
1
50
Bronx
7
4
57.1
1
1
100
6
3
50
3
2
66.7
Brooklyn
3
2
66.7
4
2
50
-
-
-
11
10
90.9
Elmhurst
2
1
50
2
1
50
7
3
42.9
-
_
_
Flushing
2
0
0
4
3
75
-
-
-
-
-
-
Harlem
3
1
33.3
3
1
33.3
21
15
71.4
-
-
-
Jewish Brooklyn
2
2
100
5
4
80
15
9
60
4
2
50
Kings County
-
-
-
-
-
-
31
15
48.4
2
1
50
Lincoln
5
1
20
3
1
33.4
3
1
33.3
3
3
100
L. 1. Jewish
6
2
33.3
9
8
88.9
-
-
-
7
5
71.4
Mt. Sinai
10
7
70
6
5
83.3
3
0
0
5
4
80
New York
13
6
46.2
4
4
100
3
3
100
1
1
100
Queens Gen.
3
2
66.7
6
6
100
10
7
70
4
3
75
St. Vincent's (NY)
5
3
60
7
5
71.4
2
0
0
3
3
100
St. Vincent's (SI)
1
0
0
8
5
62.5
3
3
100
6
4
66.7
TOTALS
70
34
48.6
64
47
73.4
116
66
56.9
52
40
76.9
Survival Rate (1251-1500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Q 1
Q - r\ .♦
No.
%
No.
%
No.
%
No.
%
Babies
6
4
66.7
7
7
100
5
4
80
2
1
50
Bellevue
7
6
85.7
9
9
100
4
4
100
6
5
83.3
Bronx
14
9
64.3
6
5
83.3
10
9
90
-
-
-
Brooklyn
6
5
83.3
10
10
100
1
1
100
13
12
92.3
Elmhurst
7
3
42.9
8
5
62.5
3
2
66.7
2
2
100
Flushing
10
9
90
9
6
66.7
2
2
100
1
1
100
Harlem
3
1
33.3
4
4
100
23
19
82.6
3
3
100
Jewish Brooklyn
6
5
83.3
6
6
100
22
17
77.3
11
9
81.8
Kings County
1
1
100
6
6
100
40
32
80
6
5
83.3
Lincoln
7
4
57.1
2
1
50
6
5
83.3
5
4
80
L. 1. Jewish
3
2
66.7
15
9
73.3
1
1
100
9
8
88.9
Mt. Sinai
13
10
76.9
11
10
90.9
7
5
71.4
9
9
100
New York
13
9
69.2
8
7
87.5
4
4
100
6
6
100
Queens Gen.
1
1
100
10
10
100
21
18
85.7
4
4
100
St. Vincent's (NY)
2
2
100
16
14
87.5
1
1
100
7
7
100
St. Vincent's (SI)
5
4
80
8
6
75
1
1
100
4
4
100
TOTALS
104
75
72.1
135
115
85.1
151
125
82.8
88
80
90.9
12-74
Table 9. City of New York Premature Center Statistics Survival Percentages (by Weight) 1969
Total All Centers
-
White
Weight Group
Born In
No. Survived
% Survival
Born Out
No. Survived
% Survival
Under 500 gms.
14
0
0
3
0
0
501-750 gms.
37
2
5.4
14
1
7.1
751-1000 gms.
55
10
18.2
37
19
51.4
1001 -1250 gms.
84
41
48.8
87
58
66.7
1251-1500 gms.
98
67
68.4
120
101
84.2
1501-1 750 gms.
150
119
79.3
214
198
92.5
1751-2000 gms.
322
302
93.8
231
210
90.9
2001-2500 gms.
1345
1309
97.3
125
110
88.0
TOTALS
2105
1850
87.9
831
697
83.9
Nonwhite
Under 500 gms.
95
0
0
4
0
0
501-750 gms.
93
3
3.2
20
3
15
751-1000 gms.
104
32
30.8
35
6
17.1
1001-1250 gms.
113
65
57.5
61
46
75.4
1251-1500 gms.
160
135
84.4
98
82
83.7
1501-1 750 gms.
194
168
86.6
128
117
91.4
1751-2000 gms.
312
303
97.1
189
181
95.8
2001-2500 gms.
1156
1140
98.6
263
261
99.2
TOTALS
2227
1846
82.9
798
696
87.2
White and Nonwhite
Under 500 gms.
109
0
0
7
0
0
501-750 gms.
130
5
3.8
34
4
11.8
751-1000 gms.
159
42
26.4
72
25
34.7
1001-1 250 gms.
197
106
53.8
148
104
70.3
1251-1 500 gms.
258
202
78.3
218
183
83.9
1501-1750 gms.
344
287
83.4
342
315
92.1
1751-2000 gms.
634
605
95.4
420
391
93.1
2001-2500 gms.
2501
2449
97.9
388
371
95.6
TOTALS
4332
3696
85.3
1629
1393
85.5
Survival Rate (Under 500 grams)
Hospital
White
Nonwhite
Survival
Survival
Su
vival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
2
0
0
_
_
_
3
0
0
_
-
-
Bellevue
-
-
-
-
-
-
-
-
-
-
-
-
Bronx
1
0
0
1
0
0
1
0
0
-
-
-
Brooklyn
-
-
-
-
-
2
0
0
1
0
0
Elmhurst
-
-
-
1
0
0
2
0
0
1
0
0
Flushing
1
0
0
-
-
-
-
-
-
-
-
Harlem
4
0
0
-
-
-
23
0
0
1
0
0
Jewish Brooklyn
-
-
—
—
-
-
-
-
-
-
-
-
Kings County
2
0
0
-
-
-
59
0
0
-
-
-
Lincoln
—
—
—
—
—
—
2
0
0
—
—
—
L. 1. Jewish
-
-
-
-
-
_
-
-
-
-
-
-
Mt. Sinai
1
0
0
—
-
—
_
—
_
-
-
—
New York
1
0
0
1
0
0
_
-
_
-
-
-
Queens Gen.
1
0
0
_
—
-
3
0
0
-
—
-
St. Vincent's (NY)
_
-
_
_
-
-
_
_
_
2
0
0
St. Vincent's (SI)
1
0
0
-
-
-
-
-
-
-
-
-
TOTALS
14
0
0
3
0
0
95
0
0
5
0
0
12-75
Table 9 (Continued)
Survival Rate (501-750 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
2
2
100
_
_
_
4
0
0
_
_
_
Bellevue
1
0
0
-
-
-
-
-
_
-
-
-
Bronx
1
0
0
2
0
0
1
0
0
-
-
-
Brooklyn
3
0
0
1
0
0
3
0
0
1
0
0
Elmhurst
3
0
0
3
0
0
2
0
0
1
0
0
Flushing
5
0
0
-
-
-
1
0
0
-
-
-
Harlem
-
-
-
-
-
-
18
2
n.i
1
0
0
Jewish Brooklyn
1
0
0
-
-
-
4
0
0
-
-
-
Kings County
1
0
0
-
-
-
38
1
2.6
2
0
0
Lincoln
1
0
0
2
0
0
5
0
0
-
-
-
L. 1. Jewish
4
0
0
1
1
100
1
0
0
3
1
33.3
Mt. Sinai
5
0
0
-
-
-
-
-
-
4
1
25
New York
7
0
0
3
0
0
4
0
0
1
0
0
Queens Gen.
-
-
-
1
0
0
10
0
0
4
0
0
St. Vincent's (NY)
-
-
-
1
0
0
2
0
0
2
0
0
St. Vincent's (SI)
TOTALS
3
37
0
2
0
14
1
-
93
3
-
1
20
1
3
100
15
5.4
7.1
3.2
Survival Rate (751-1000 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
6
0
0
_
_
_
_
_
_
_
_
_
Bellevue
1
1
100
3
2
66.7
-
-
-
3
0
0
Bronx
4
1
25
4
1
25
8
0
0
1
0
0
Brooklyn
4
0
0
-
-
-
3
1
33.3
5
1
20
Elmhurst
5
1
20
3
2
66.7
2
0
0
-
-
-
Flushing
2
0
0
4
2
50
2
1
50
1
0
0
Harlem
-
-
-
1
0
0
16
3
18.7
-
-
-
Jewish Brooklyn
3
2
66.7
1
1
100
22
12
54.6
2
0
0
Kings County
4
1
25
3
2
33.3
31
7
22.6
10
3
30
Lincoln
3
1
33.3
_
-
-
4
1
25
1
0
0
L. 1. Jewish
3
0
0
2
1
50
-
-
-
5
1
20
Mt. Sinai
7
0
0
3
1
63.3
1
1
100
1
0
0
New York
5
2
40
4
2
50
4
2
50
1
0
0
Queens Gen.
1
0
0
2
1
50
11
4
36.4
3
1
33.3
St. Vincent's (NY)
_
_
_
4
2
50
_
_
_
2
0
0
St. Vincent's (SI)
TOTALS
7
55
1
10
14.3
3
37
2
19
66.7
104
32
-
35
6
-
18.2
51.4
30.8
17.1
Table 9 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
12
2
16.7
3
1
33.3
7
3
42.9
2
0
0
Bellevue
5
1
20
8
5
62.5
3
1
33.3
3
3
100
Bronx
3
1
33.3
6
4
66.7
3
1
33.3
4
4
100
Brooklyn
3
1
33.3
5
3
60
-
-
-
7
4
57.1
Elmhurst
5
2
40
5
3
60
1
0
0
4
4
100
Flushing
6
4
66.7
4
3
75
_
-
-
4
4
100
Harlem
1
0
0
2
0
0
19
13
68.4
3
2
66.7
Jewish Brooklyn
5
4
80
4
2
50
27
16
59.3
4
3
75
Kings County
3
3
100
4
3
75
28
15
53.6
8
5
62.5
Lincoln
2
0
0
2
2
100
4
2
50
-
-
-
L. 1. Jewish
5
4
80
16
11
68.7
_
-
-
5
3
60
Mt. Sinai
8
5
62.5
5
4
80
1
1
100
4
3
75
New York
16
10
62.5
11
7
63.6
4
4
100
3
3
100
Queens Gen.
2
1
50
-
-
-
12
6
50
4
3
75
St. Vincent's (NY)
2
1
50
6
6
100
3
2
66.7
4
3
75
St. Vincent's (SI)
6
2
33.3
6
4
66.7
1
1
100
2
2
100
TOTALS
84
41
48.8
87
58
66.7
113
65
57.5
61
46
75.4
Survival Rate (1251-1500 grams)
Hospital
White
Nonwhite
Born In
Survival
Born Out
Survival
Survival
Born Out
Survival
No.
%
No.
%
No.
%
No.
%
Babies
10
7
70
6
4
66.7
14
12
85.7
5
5
100
Bellevue
8
6
75
13
10
76.9
8
6
75
6
5
83.3
Bronx
10
9
90
7
5
71.4
7
7
100
2
2
100
Brooklyn
4
4
100
11
9
81.8
4
4'
100
14
11
78.6
Elmhurst
6
3
50
5
5
100
5
4
80
2
2
100
Flushing
3
1
33.3
5
5
100
1
1
100
2
2
100
Harlem
_
_
_
3
3
100
19
15
78.9
4
4
100
Jewish Brooklyn
9
4
44.4
10
8
80
19
19
100
11
8
72.7
Kings County
-
-
_
5
4
80
35
28
80
8
7
87.5
Lincoln
5
4
80
4
3
75
10
5
50
3
3
100
L. 1. Jewish
9
6
66.7
15
15
100
-
-
-
9
5
55.5
Mt. Sinai
15
12
80
7
7
100
4
2
50
4
4
100
New York
10
6
60
8
6
75
7
7
100
6
5
83.3
Queens Gen.
-
_
_
7
6
85
24
22
91.7
9
9
100
St. Vincent's (NY)
7
4
57.1
9
7
77.8
2
2
100
5
5
100
St. Vincent's (SI)
TOTALS
2
98
1
67
50
5
120
4
101
80
1
160
1
135
100
8
98
5
82
62.5
68.4
84.2
84.4
83.7
12-77
Table 10. City of New York Premature Center Statistics Survival Percentages (by Weight) 1970
Total All Centers
White
Weight Group
Born In
No. Survived
% Survival
Born Out
No. Survived
% Survival
Under 500 gms.
11
0
0
1
0
0
501-750 gms.
33
0
0
12
1
8.3
751-1000 gms.
61
12
19.7
39
18
46.2
1001-1250 gms.
76
35
46.1
81
49
60.5
1251-1500 gms.
103
71
68.9
118
98
83.1
1501-1750 gms.
172
154
89.5
202
179
88.6
1751-2000 gms.
271
247
91.1
228
211
92,5
2001-2500 gms.
1323
1291
97.6
133
126
94.7
TOTALS
2050
1810
88.3
814
682
83.8
Nonwhite
Under 500 gms.
63
0
0
3
0
0
501-750 gms.
80
0
0
7
0
0
751-1000 gms.
99
27
27.3
40
22
55
1001-1 250 gms.
122
75
61.5
62
47
75.8
1251-1500 gms.
164
125
76.2
104
95
91.3
1501 -1750 gms.
219
205
93.6
153
144
94.1
1751-2000 gms.
319
308
96.6
185
180
97.3
2001 -2500 gms.
1470
1451
98.7
81
75
92.6
TOTALS
2536
2191
86.4
635
563
88.7
White and Nonwhite
Under 500 gms.
74
0
0
4
0
0
501-750 gms.
113
0
0
19
1
5.3
751-1000 gms.
160
39
24.4
79
40
50.6
1001-1250 gms.
198
110
55.6
143
96
67.1
1251-1500 gms.
267
196
73.4
222
193
86.9
1501-1750 gms.
391
359
91.8
355
323
91
1751-2000 gms.
590
555
94.1
413
391
94.7
2001-2500 gms.
2793
2742
98.2
214
201
13.9
TOTALS
4586
4001
87.2
1449
1245
85.9
Survival Rate (Under 500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
1
0
0
-
-
-
-
_
_
_
_
_
Bellevue
-
-
-
-
-
-
-
-
-
-
-
-
Bronx
—
—
—
—
—
—
—
—
—
—
—
—
Brooklyn
1
0
0
-
-
-
-
-
-
-
-
-
Elmhurst
-
-
-
-
-
-
-
-
-
-
-
-
Flushing
—
—
—
—
—
—
—
—
—
—
—
—
Harlem
1
0
0
-
-
-
16
0
0
-
-
-
Jewish Brooklyn
-
-
_
-
-
-
2
0
0
-
-
-
Kings County
2
0
0
-
-
-
40
0
0
1
0
0
Lincoln
2
0
0
—
—
—
—
—
—
—
—
—
L. 1. Jewish
-
_
_
-
—
—
—
—
—
-
-
—
Mt. Sinai
3
0
0
-
-
-
-
-
-
-
-
-
New York
—
—
—
—
—
—
—
—
—
—
—
—
Oueens Gen.
-
_
_
-
-
-
5
0
0
1
0
0
St. Vincent's (NY)
1
0
0
-
—
—
-
_
1
0
0
St. Vincent's (SI)
-
-
-
1
0
0
-
-
-
-
-
-
TOTALS
11
0
0
1
0
0
63
0
0
3
0
0
Table 10 (Continued)
Survival Rate (501-750 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
2
0
0
_
_
_
1
0
0
1
0
0
Bellevue
1
0
0
-
-
-
2
0
0
-
-
-
Bronx
3
0
0
-
-
-
2
0
Q
-
-
-
Brooklyn
1
0
0
-
-
-
3
0
0
2
0
0
Elmhurst
2
0
0
3
0
0
_
-
_
-
-
Flushing
4
0
0
-
-
-
1
0
0
-
-
-
Harlem
-
—
-
-
-
-
19
0
0
_
-
-
Jewish Brool<lyn
2
0
0
-
-
-
3
0
0
-
-
-
Kings County
2
0
0
2
0
0
29
0
0
2
0
0
Lincoln
6
0
0
-
-
-
1
0
0
-
-
-
L. 1. Jewish
-
-
-
-
-
-
-
-
-
-
-
-
IVIt. Sinai
2
0
0
2
1
50
2
0
0
1
0
0
New York
6
0
0
5
0
0
-
-
-
-
-
-
Queens Gen.
2
0
0
-
-
-
17
0
0
1
0
0
St. Vincent's (NY)
-
-
-
-
-
-
-
-
-
-
-
-
St. Vincent's (SI)
TOTALS
33
0
-
12
1
-
80
0
-
7
0
0
0
8.3
0
Survival Rate (751-1000
grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
9
0
0
1
1
100
4
1
25
_
-
_
Bellevue
-
-
2
1
50
3
2
86.7
1
1
100
Bronx
9
3
33.3
4
2
50
7
0
0
1
0
0
Brooklyn
2
0
0
1
1
100
2
0
0
6
4
66.7
Elmhurst
5
1
20
1
0
0
1
0
0
1
0
0
Flushing
4
1
25
-
-
-
1
0
0
2
1
50
Harlem
-
-
-
-
-
25
5
20
-
-
-
Jewish Brooklyn
3
0
0
3
1
33.3
9
4
44.4
5
5
100
Kings County
-
-
-
1
0
0
31
8
25.8
7
1
15
Lincoln
6
0
0
_
_
_
4
2
50
-
-
-
L. 1. Jewish
-
-
-
6
3
50
-
-
-
2
2
100
Mt. Sinai
11
3
27.3
5
2
40
1
0
0
5
3
60
New York
5
2
40
2
1
50
_
-
_
1
1
100
Queens Gen.
2
1
50
3
1
33.3
10
4
40
5
3
60
St. Vincent's (NY)
1
0
0
4
1
25
_
_
_
2
1
50
St. Vincent's (SI)
4
1
25
6
4
66.7
1
1
100
2
0
0
TOTALS
61
12
19.7
39
18
46.2
99
27
27.3
40
22
55
12-79
Table 10 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
9
5
55.6
3
2
66.7
7
4
57.1
_
_
_
Bellevue
1
1
100
5
4
80
-
-
-
2
2
100
Bronx
7
2
28.6
7
4
57.1
8
7
87.5
2
2
100
Brooklyn
2
0
0
4
1
25
1
0
0
8
5
62.5
Elmliurst
8
5
62.5
1
0
0
1
1
100
2
1
50
Flushing
4
2
50
2
0
0
-
-
-
6
5
83.3
Harlem
1
1
100
2
2
100
25
19
76
1
0
0
Jewish Brooklyn
3
1
33.3
3
2
66.7
12
10
83.3
7
5
71.4
Kings County
1
1
100
-
-
-
40
17
42.5
5
3
60
Lincoln
7
3
94.3
1
0
0
4
2
50
_
_
_
L. 1. Jewish
2
0
0
6
3
50
1
1
100
8
5
62.5
Mt. Sinai
10
5
50
5
4
80
2
2
100
3
3
100
New York
16
8
50
17
9
52.9
4
2
50
7
6
85.7
Queens Gen.
-
-
_
4
2
50
13
8
61.5
5
4
80
St. Vincent's (NY)
2
0
0
11
8
72.7
1
0
0
3
3
100
St. Vincent's (SI)
TOTALS
3
76
1
35
33.3
46.1
10
81
8
49
80
3
122
2
75
66.7
61.5
3
62
3
47
100
60.4
75.8
Survival Rate (1251
-1500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
16
9
56.2
4
3
75
12
12
100
_
_
_
Bellevue
4
3
75
7
6
85.7
1
1
100
5
5
100
Bronx
9
7
77.8
5
3
60
1
10
90.9
_
-
-
Brooklyn
8
5
62.5
9
7
77.8
2
2
100
22
22
100
Elmhurst
10
6
60
6
5
83.3
7
7
100
1
1
100
Flushing
4
4
100
7
6
85.7
3
2
66.7
1
1
100
Harlem
-
-
-
1
1
100
29
22
75.9
2
2
100
Jewish Brooklyn
3
2
66.7
3
3
100
15
11
73.3
6
4
66.7
Kings County
3
3
100
-
-
-
49
34
69.4
8
7
87.5
Lincoln
7
4
57.1
1
1
100
13
7
53.8
1
1
100
L. 1. Jewish
5
5
100
23
20
87
-
-
-
13
12
92.3
Mt. Sinai
15
12
80
3
3
100
7
7
100
5
5
100
New York
8
5
62.5
17
13
76.5
3
2
66.7
17
16
94.2
Queens Gen.
1
1
100
9
8
88.9
7
5
71.4
5
5
100
St. Vincent's (NY)
6
3
50
14
11
78.6
2
-
-
13
10
76.9
St. Vincent's (Si)
TOTALS
4
103
2
71
50
9
118
8
98
88.9
3
164
3
125
100
5
104
4
95
80
68.9
83.1
76.2
91.3
12-80
Table 11. City of New York Premature Center Statistics Survival Percentages (by Weight) 1971
Total All Centers
White 1
Weight Group
Born In
No. Survived
% Survival
Born Out
No. Survived
% Survival
Under 500 gms.
7
0
0
2
0
0
501-750 gms.
44
1
2.3
11
0
0
751-1000 gms.
52
9
17.3
34
12
35.3
1001-1250 gms.
74
27
36.5
75
52
69.3
1251-1500 gms.
82
58
70.7
85
69
81.2
1501-1750 gms.
158
134
84,8
144
127
88.2
1751-2000 gms.
237
216
91.1
217
205
94.5
2001-2500 gms.
1182
1147
97.0
164
141
86.0
TOTALS
1836
1592
86.7
732
606
82.8
Nonwhite
Under 500 gms.
28
0
0
1
0
0
501-750 gms.
63
3
4.8
14
2
14.3
751-1000 gms.
88
17
19.3
43
15
34.9
1001-1250 gms.
92
63
68.5
59
44
74.6
1251-1500 gms.
140
116
82.9
94
82
87.2
1501-1750 gms.
193
183
94.8
133
120
90.2
1751-2000 gms.
271
258
95.2
189
185
97.9
2001-2500 gms.
1205
1192
98.9
127
122
96.1
TOTALS
2080
1832
88.1
660
570
86,4
White and Nonwhite
Under 500 gms.
35
0
0
3
0
0
501-750 gms.
107
4
3,7
25
2
8,0
751-1000 gms.
140
26
18,6
77
27
35.1
1001-1250 gms.
166
90
54,2
134
96
71.6
1251-1500 gms.
222
174
78,4
179
151
84,4
1501-1750 gms.
351
317
90.3
277
247
89,2
1751-2000 gms.
508
474
93.3
406
390
96,1
2001-2500 gms.
2387
2339
98.0
291
263
90.4
TOTALS
3916
3424
87,4
1392
1176
84.5
Survival Rate (Under 500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
2
0
0
_
_
-
-
-
_
_
_
Bellevue
1
0
0
-
-
-
-
-
-
-
-
Bronx
-
—
—
1
0
0
2
0
0
—
-
—
Brooklyn
1
0
0
-
-
-
-
-
-
-
-
-
Elmhurst
-
-
-
-
-
-
-
-
-
-
-
-
Flushing
—
—
—
—
—
—
—
—
—
—
—
—
Harlem
—
—
—
—
—
—
5
0
0
-
-
—
Jewish Brooklyn
-
-
-
-
-
-
1
u
0
-
-
-
Kings County
3
0
0
-
-
-
16
0
0
-
-
-
Lincoln
—
—
—
—
—
—
—
—
—
—
—
—
L. 1. Jewish
-
-
-
-
-
-
1
0
0
-
-
-
Mt. Sinai
—
—
—
—
—
—
—
—
—
—
—
—
New York
-
-
-
1
0
0
-
-
-
1
0
0
Queens Gen.
—
—
—
—
—
—
1
0
0
—
—
—
St. Vincent's (NY)
-
-
-
-
-
-
2
0
0
-
-
-
St. Vincent's (SI)
-
-
-
-
-
-
-
-
—
-
-
-
TOTALS
7
0
0
2
0
0
28
0
0
1
0
0
12-81
Table 11 (Continued)
Survival Rate (501-750 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
4
0
0
_
_
_
2
0
0
_
_
_
Bellevue
1
0
0
1
0
0
-
-
-
-
-
Bronx
5
1
20
-
-
-
3
0
0
1
0
0
Brooklyn
4
0
0
-
-
-
1
1
100
3
1
33.3
Elmhurst
-
-
-
1
0
0
2
0
0
1
0
0
Flushing
3
0
0
-
-
-
-
-
-
-
-
-
Harlem
-
-
_
-
-
_
13
1
7.7
_
_
_
Jewish Brooklyn
1
0
0
-
-
-
5
0
0
4
0
0
Kings County
6
0
0
-
-
-
16
0
0
-
-
-
Lincoln
4
0
0
-
-
-
_
_
_
-
_
_
L. 1. Jewish
2
0
0
3
0
0
_
_
_
_
_
_
Mt. Sinai
5
0
0
2
0
0
1
0
0
1
0
0
New York
3
0
0
3
0
0
4
0
0
4
1
25
Queens Gen.
6
0
0
-
-
-
14
1
7.1
-
-
-
St. Vincent's (NY)
-
-
-
1
0
0
2
0
0
-
-
-
St. Vincent's (SI)
-
-
-
-
-
-
-
-
-
-
-
-
TOTALS
44
1
2.3
11
0
0
63
3
4.8
14
2
14.3
Su
rvival Rate (751-
1000 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
1
0
0
3
0
0
5
0
0
2
1
50
Bellevue
1
0
0
2
0
0
-
-
-
3
2
66.7
Bronx
6
0
0
-
-
-
8
1
12.5
-
-
-
Brooklyn
-
-
-
3
1
33.3
1
0
0
3
2
66.7
Elmhurst
1
1
100
2
1
50
-
-
-
-
-
-
Flushing
3
1
33.3
-
-
-
2
1
50
1
1
100
Harlem
-
-
-
1
0
0
15
3
20
1
0
0
Jewish Brooklyn
1
0
0
4
2
50
5
3
60
7
0
0
Kings County
5
0
0
-
-
-
30
5
16.7
4
0
0
Lincoln
10
2
20
1
1
100
0
-
-
-
-
-
L. 1. Jewish
8
1
12.5
6
3
50
-
-
-
3
0
0
Mt. Sinai
5
2
40
6
2
33.3
1
0
0
5
2
40
New York
3
0
0
4
2
50
1
0
0
12
5
41.7
Queens Gen.
5
2
40
-
-
-
14
2
14.3
-
-
-
St. Vincent's (NY)
-
-
-
1
0
0
4
2
50
2
2
100
St. Vincent's (SI)
TOTALS
3
52
0
9
0
1
34
0
12
0
2
88
0
17
0
43
15
-
17.3
35.3
19.3
34.9
Table 11 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
7
2
28.6
5
3
60
5
4
80
-
-
-
Bellevue
6
2
33.3
5
3
60
-
-
-
8
6
75
Bronx
6
2
33.3
9
5
55.6
3
3
100
-
-
-
Brool<lyn
5
2
40
4
4
100
4
3
75
13
11
84.6
Elmliurst
2
1
50
2
1
50
3
2
66.7
2
2
100
Flushing
6
4
66.7
3
1
33.3
2
1
50
1
1
100
Harlem
-
-
-
-
-
-
18
17
94.4
1
0
0
Jewish Brooklyn
1
1
100
4
3
75
7
3
42.9
9
6
66.7
Kings County
4
0
0
2
2
100
19
10
52.6
6
5
83.3
Lincoln
8
3
37.5
-
-
-
6
5
83.3
-
-
-
L. 1. Jewish
11
6
54.5
10
9
90
1
0
0
10
7
70
Mt. Sinai
11
3
27.3
10
7
70
4
3
75
4
2
50
New York
4
1
25
12
8
66.7
2
1
50
1
0
0
Queens Gen.
2
0
0
2
2
100
15
9
60
1
1
100
St. Vincent's (NY|
-
-
-
3
1
33.3
3
2
66.7
3
3
100
St. Vincent's (SI)
1
0
0
4
3
75
-
-
-
-
-
-
TOTALS
74
27
36.5
75
52
69.3
92
63
68.5
59
44
74.6
Survival Rate (1251-1500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
5
2
40
2
2
100
7
7
100
1
1
100
Bellevue
10
7
70
11
8
72.7
1
1
100
8
5
62.5
Bronx
13
10
76.9
5
3
60
12
10
83.3
2
2
100
Brooklyn
4
0
0
7
6
85.7
2
2
100
16
15
93.7
Elmhurst
2
1
50
-
-
-
1
0
0
2
1
50
Flushing
8
7
87.5
7
7
100
1
1
100
2
2
100
Harlem
-
-
-
-
-
-
27
26
96.3
3
3
100
Jewish Brooklyn
4
4
100
6
5
83.3
20
18
90
19
17
89.5
Kings County
6
5
83.3
1
0
0
37
24
64.9
13
10
76.9
Lincoln
8
6
75
-
-
-
8
5
62.5
-
-
-
L. 1. Jewish
2
1
50
10
9
90
-
-
-
4
3
75
Mt. Sinai
8
5
62.5
8
6
75
3
3
100
7
7
100
New York
5
5
100
11
10
90.9
4
3
75
6
5
83.3
Queens Gen.
-
-
-
3
2
66.7
13
12
92.3
4
4
100
St. Vincent's (NY)
2
2
100
4
3
75
2
2
100
5
5
100
St. Vincent's (Sll
5
3
60
10
8
80
2
2
100
2
2
100
TOTALS
82
58
70.7
85
69
81.2
140
116
82.9
94
82
87.2
Table 12. City of New York Premature Center Statistics Survival Percentages (by Weight) 1972
Total All Centers
White 1
Weight Group
Born In
No. Survived
% Survival
Born Out
No. Survived
% Survival
Under 500 gms.
14
1
7.1
1
0
0
501-750 gms.
27
2
7.4
20
4
20
751-1000 gms.
51
13
25.5
55
26
47.3
1001-1250 gms.
65
34
52.3
65
41
63.1
1251-1500 gms.
83
57
68.6
94
72
76.6
1501-1750 gms.
133
118
88.7
154
138
89.6
1751 -2000 gms.
215
200
93.0
169
154
91.1
2001-2500 gms.
951
929
97.7
163
146
89.6
TOTALS
1539
1354
87.9
721
581
80.6
Nonwhite |
Under 500 gms.
26
0
0
3
0
0
501-750 gms.
53
1
1.9
14
2
14.3
751-1000 gms.
82
24
29.3
51
31
60.8
1001-1250 gms.
85
43
50.6
70
43
61.4
1251-1 500 gms.
94
74
78.7
76
64
84.2
1501-1 750 gms.
160
137
85.6
127
117
92.1
1751-2000 gms.
253
243
96.0
171
166
97.1
2001-2500 gms.
973
958
98.5
129
124
96.1
TOTALS
1726
1480
85.7
641
547
85.3
White and Nonwhite
Under 500 gms.
39
0
0
4
0
0
501 -750 gms.
80
3
3.7
34
6
17.6
751-1000 gms.
133
37
27.8
106
57
53.8
1001-1250 gms.
150
77
51.3
135
84
62.2
1251-1500 gms.
177
131
74.0
170
136
80.0
1501-1750 gms.
293
255
87.0
281
255
90.7
1751-2000 gms.
468
443
94.7
340
320
94.1
2001-2500 gms.
1924
1888
98.1
292
270
92.5
TOTALS
3264
2834
86.8
1362
1128
82.8
Survival Rate (500 grams)
Hospital
White
Nonwhite
Born In
Survival
Born Out
Survival
Born In
Survival
Born Out
Survival J
No.
%
No.
%
No.
%
No.
%
Babies
_
_
_
_
_
_
_
_
_
_
_
_
Bellevue
-
_
1
0
0
1
0
0
-
_
_
Bronx
1
0
0
-
-
-
1
0
0
-
_
-
Brooklyn
4
0
0
-
-
-
-
-
-
-
-
-
Elmhurst
-
-
_
—
-
-
-
-
-
-
-
-
Flushing
—
—
—
—
—
—
—
-
-
-
—
—
Harlem
—
—
—
—
—
—
2
0
0
—
—
—
Jewish Brooklyn
Kings County
""
~
-
_
~
_
15
0
0
2
0
0
Lincoln
2
0
0
—
—
—
—
—
—
—
—
—
L. 1. Jewish
3
0
0
—
—
—
—
—
—
—
—
—
Mt. Sinai
2
0
0
-
-
-
1
0
0
1
0
0
New York
-
—
—
-
-
—
—
—
-
—
—
—
Queens Gen.
-
-
-
-
-
-
6
0
0
-
-
-
St, Vincent's (NY)
1
1
100
-
—
—
_
_
—
-
-
—
St. Vincent's (SI)
TOTALS
1
14
0
0
1
~0
-
~26
~0
-
~~3
~0
-
7.1
0
0
0
12-84
Table 12 (Continued)
Survival Rate (501-750 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
1
0
0
_
_
_
7
0
0
2
0
0
Bellevue
1
0
0
-
-
-
-
_
_
1
0
0
Bronx
2
0
0
1
0
0
2
0
0
_
_
_
Brooklyn
2
0
0
1
0
0
2
0
0
2
0
0
Elmhurst
1
0
0
_
_
_
1
0
0
_
_
_
Flushing
-
-
_
2
1
50
1
0
0
_
_
_
Harlem
_
_
_
_
_
_
8
0
0
_
_
_
Jewish Brooklyn
1
0
0
4
1
25
3
0
0
5
0
0
Kings County
3
0
0
-
-
-
19
0
0
-
_
_
Lincoln
6
2
33.3
-
-
-
2
1
50
_
_
_
L. 1. Jewish
2
0
0
1
0
0
-
-
-
2
1
50
IVIt. Sinai
-
-
-
2
0
0
_
_
_
_
_
_
New York
2
0
0
7
1
14.3
1
0
0
1
1
50
Queens Gen.
1
0
0
-
-
_
4
0
0
_
_
_
St. Vincent's (NY)
2
0
0
2
1
50
-
_
_
_
_
_
St. Vincent's (SI)
3
0
0
-
-
-
3
0
0
1
0
0
TOTALS
27
2
7.4
20
4
20
53
1
1.9
14
2
14.3
Survival Rate (751-1000 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Q „ r» ♦
No.
%
No.
%
No.
%
No.
%
Babies
-
-
-
3
2
66.7
7
1
14.3
4
2
50
Bellevue
2
0
0
4
1
25
-
-
-
3
1
33.3
Bronx
1
0
0
2
2
100
9
3
33.3
1
1
100
Brooklyn
2
0
0
1
1
100
1
1
100
5
4
80
Elmhurst
8
1
12.5
-
_
-
2
1
50
_
_
_
Flushing
3
1
33.3
-
-
_
_
_
_
-
_
_
Harlem
-
-
-
1
0
0
20
5
25
2
2
100
Jewish Brooklyn
2
0
0
8
3
37.5
5
1
20
13
10
76.9
Kings County
6
0
0
1
1
100
17
3
17.6
1
0
0
Lincoln
6
2
33.3
-
_
_
5
3
60
_
_
_
L. I.Jewish
5
3
60
8
3
37.5
1
0
0
9
5
55.6
Mt. Sinai
2
1
50
9
4
44.4
2
1
50
4
2
50
New York
9
4
44.4
16
8
50
_
_
_
6
3
50
Queens Gen.
1
0
0
1
0
0
11
5
45.5
_
St. Vincent's (NY)
2
1
50
_
_
_
1
0
0
1
0
0
St. Vincent's (SI)
TOTALS
2
51
0
13
0
1
55
1
26
100
1
82
0
24
0
2
51
1
31
50
60.8
25.5
47.3
29.3
12-85
Table 12 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
rj r\ *
No.
%
No.
%
No.
%
No.
%
Babies
3
0
0
_
-
_
1
0
0
1
1
100
Bellevue
1
0
0
6
3
50
3
2
66.7
3
3
100
Bronx
7
4
57.1
3
2
66.7
5
0
0
3
3
100
Brooklyn
4
3
75
4
2
50
2
1
50
14
8
57.1
Elmiiurst
4
3
75
-
-
-
1
0
0
_
-
-
Fiustning
4
2
50
3
3
100
-
-
-
-
-
-
Harlem
1
1
TOO
-
-
-
26
10
38.5
1
1
100
Jewisii Brooklyn
2
0
0
5
1
20
13
9
69.2
15
7
46.7
Kings County
-
-
-
-
-
-
16
9
56.2
1
1
100
Lincoln
11
5
45.5
_
-
-
5
3
60
_
_
_
L. 1. Jewish
5
3
60
14
11
78.6
-
_
-
12
6
50
IVlt. Sinai
10
7
70
8
5
62,5
3
3
100
8
6
75
New York
4
3
75
13
10
76.9
3
2
66.7
8
4
50
Queens Gen.
1
1
100
-
-
-
6
3
50
1
1
100
St. Vincent's (NY)
2
1
50
4
2
50
-
_
_
3
2
66.7
St. Vincent's (SI)
TOTALS
6
65
1
34
16.7
5
65
2
41
40
1
85
1
43
100
70
43
-
52.3
63.1
50.6
61.4
Survival Rate (1251-1500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
10
4
40
6
5
83.3
7
3
42.9
3
2
66.7
Bellevue
5
4
80
10
5
50
-
-
-
3
3
100
Bronx
6
6
100
7
4
57.1
7
7
100
2
0
0
Brooklyn
7
6
85.7
8
8
100
3
2
66.7
15
12
80
Elmhurst
5
2
40
2
2
100
3
3
100
4
3
75
Flushing
5
5
100
4
3
75
2
1
50
1
0
0
Harlem
-
-
-
-
-
-
21
18
85.7
1
1
100
Jewish Brooklyn
2
1
50
4
1
25
8
7
87.5
17
15
88.2
Kings County
6
4
66.7
1
1
100
20
16
80
1
1
100
Lincoln
12
10
83.3
-
-
-
4
4
100
-
-
-
L. 1. Jewish
6
5
83.3
19
15
78.9
-
-
-
9
8
88.9
Mt. Sinai
9
6
66.7
8
6
75
4
3
75
8
8
100
New York
3
1
33.3
10
8
80
3
2
66.7
5
4
80
Queens Gen.
2
1
50
2
1
50
9
6
66.7
4
4
100
St. Vincent's (NY)
3
2
66.7
5
5
100
2
1
50
1
1
100
St. Vincent's (SI)
2
0
0
8
8
100
1
1
100
2
2
100
TQTALS
83
57
68.7
94
72
76.6
94
74
78.7
76
64
84.2
12-86
Table 13. City of nIw York Premature Center Statistics Survival Percentages (by Weight) 1973
Total All Centers
White 1
Weight Group
Born In
No. Survived
% Survival
Korn Out
No. Survived
% Survival
Under 500 gms.
6
0
0
1
0
0
501-750 gms.
21
2
9.5
21
5
23.8
751-1000 gms.
41
12
29.3
46
26
56.5
1001-1250 gms.
55
34
61.8
60
37
61.7
1251-1500 gms.
67
53
79.1
103
74
71.8
1501-1750 gms.
123
107
87.0
142
126
88.7
1751-2000 gms.
204
189
92.6
160
142
88.8
2001-2500 gms.
641
616
96.1
160
135
84.4
TOTALS
1158
1013
87.5
693
545
78.6
Nonwhite 1
Under 500 gms.
16
0
0
2
0
0
501-750 gms.
29
3
10.3
13
1
7.7
751-1000 gms.
57
25
43.9
41
23
56.1
1001-1250 gms.
77
43
55.8
47
33
70,2
1251-1500 gms.
78
61
78.2
74
60
81.1
1501-1750 gms.
174
161
92.5
115
106
92.2
1751-2000 gms.
242
232
95.9
156
147
94.2
2001-2500 gms.
809
787
97.3
114
109
95.6
TOTALS
1482
1312
88.5
562
479
85.2
White and Nonwhite
Under 500 gms.
22
0
0
3
0
0
501-750 gms.
50
5
10.0
34
6
17.6
751-1000 gms.
98
37
37.8
87
49
56.3
1001-1 250 gms.
132
77
58.3
107
70
65.4
1251 -1500 gms.
145
114
78.6
177
134
75.7
1501-1750 gms.
297
268
90.2
257
232
90.3
1751-2000 gms.
446
421
94.4
316
289
91.5
2001-2500 gms.
1450
1403
96.8
274
244
89.0
TOTALS
2640
2325
88
1255
1024
81.6
Survival Rate (under 500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
-
-
-
-
-
-
-
-
_
_
_
_
Bellevue
-
-
-
-
-
-
-
-
-
-
-
-
Bronx
-
-
—
-
-
—
1
0
0
-
-
—
Brooklyn
-
-
-
-
-
-
-
-
-
-
-
-
Elmhurst
-
-
-
-
-
-
-
-
-
-
-
-
Flushing
—
—
—
—
—
—
—
—
—
—
—
—
Harlem
-
-
-
-
-
-
5
0
0
-
-
-
Jewish Brooklyn
-
-
-
1
0
0
1
0
0
1
0
0
Kings County
4
0
0
-
-
-
4
0
0
1
0
0
Lincoln
—
—
—
—
—
—
1
0
0
—
—
—
L. 1. Jewish
2
0
0
-
-
-
-
-
-
-
-
-
Mt. Sinai
—
—
—
—
—
—
—
—
—
—
—
—
New York
—
—
—
—
-
—
—
—
-
-
-
-
Queens Gen.
-
-
-
-
-
-
2
0
0
-
-
-
St. Vincent's (NY)
-
-
-
-
-
-
-
-
-
-
-
-
St. Vincent's (SI)
-
-
-
-
-
-
2
0
0
-
-
-
TOTALS
6
0
0
1
0
0
16
0
0
2
0
0
12-87
Table 13 (Continued)
Survival Rate (501-750 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Q rv..*
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
_
_
_
_
_
_
2
0
0
_
_
_
Bellevue
2
0
0
1
1
100
-
-
-
-
-
-
Bronx
-
-
-
1
0
0
4
0
0
-
-
-
Brool<lyn
6
2
33.3
1
0
0
-
-
-
3
0
0
Elmhurst
1
0
0
-
-
-
-
-
-
-
-
-
Flusliing
-
-
-
-
-
_
-
-
-
_
-
_
Harlem
-
-
-
-
_
_
5
0
0
_
_
_
Jewish Brooklyn
1
0
0
-
-
-
4
1
25
3
1
33.3
Kings County
2
0
0
-
-
-
2
0
0
-
-
-
Lincoln
-
-
-
-
_
_
1
0
0
_
_
_
L. 1. Jewish
2
0
0
5
1
20
1
0
0
3
0
0
Mt. Sinai
1
0
0
2
2
100
2
2
100
1
0
0
New York
2
0
0
7
1
14.3
-
-
-
2
0
0
Queens Gen.
1
0
0
-
_
_
7
0
0
_
_
_
St. Vincent's (NY)
1
0
0
2
0
0
-
-
-
1
0
0
St. Vincent's (SI)
2
0
0
1
0
0
1
0
0
-
-
-
TOTALS
21
2
9.5
21
5
23.8
29
3
10.3
13
1
7.7
Survival Rate (751-1000 grams)
Hospital
White
Nonwhite
Sur
vival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
4
2
50
4
2
50
6
1
16.7
1
0
0
Bellevue
3
1
33.3
6
2
33.3
-
-
-
1
0
0
Bronx
1
0
0
2
0
0
3
0
0
1
0
0
Brooklyn
3
1
33.3
2
2
100
2
1
50
5
1
20
Elmhurst
1
0
0
1
1
100
2
1
50
2
1
50
Flushing
1
0
0
1
1
100
-
-
-
-
-
-
Harlem
-
-
-
-
-
-
13
9
69.2
-
-
-
Jewish Brooklyn
1
0
0
5
2
40
11
5
45.4
10
4
40
Kings County
5
0
0
-
-
-
5
0
0
1
1
100
Lincoln
4
1
25
_
-
_
_
-
-
-
-
_
L. 1. Jewish
5
3
60
11
5
45.4
1
0
0
6
4
66.7
Mt. Sinai
7
4
57.1
2
2
100
6
2
33.3
6
6
100
New York
2
0
0
11
9
81.8
3
3
100
8
6
75
Queens Gen.
-
-
_
_
_
_
4
2
50
_
_
_
St. Vincent's (NY)
1
0
0
_
- _
1
1
100
_
_
_
St. Vincent's (SI)
3
0
0
1
0 , 0
-
-
-
-
-
-
TOTALS
41
12
29.3
46
26
56.5
57
25
43.9
41
23
56.1
12-88
Table 13 (Continued)
Survival Rate (1001-1250 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
3
1
33.3
6
2
33.3
1
0
0
1
1
100
Bellevue
2
2
100
8
5
62.5
-
-
-
-
-
-
Bronx
6
3
50
4
3
75
5
5
100
1
1
100
Brooklyn
4
2
50
3
2
66.7
5
2
40
5
4
80
Elmhurst
4
3
75
1
0
0
4
3
75
1
1
100
Flushing
1
1
100
2
1
50
-
-
-
-
-
-
Harlem
-
-
-
-
-
21
14
66.7
-
-
-
Jewish Brooklyn
1
1
100
5
2
40
6
2
33.3
11
9
81.8
Kings County
2
1
50
1
1
100
2
1
50
1
0
0
Lincoln
11
7
63.6
-
-
-
8
5
62.5
-
-
-
L. 1. Jewish
3
3
TOO
9
8
88.9
-
-
-
11
8
72.7
Mt. Sinai
4
4
100
6
3
50
5
3
60
3
3
100
New York
7
3
42.9
10
6
60
6
3
50
9
4
45
Queens Gen.
-
_
-
1
1
100
8
4
50
1
1
100
St. Vincent's (NY)
2
2
100
2
2
100
4
1
25
3
1
33.3
St. Vincent's (SI)
5
1
20
2
1
50
2
0
0
-
-
-
TOTALS
55
34
61.8
60
37
61.7
77
43
55.8
47
33
70.2
Survival Rate (1251-1500 grams)
Hospital
White
Nonwhite
Survival
Survival
Survival
Survival
Born In
Born Out
Born In
Born Out
No.
%
No.
%
No.
%
No.
%
Babies
7
4
57.1
8
4
50
5
5
100
2
1
50
Bellevue
11
8
72.7
4
3
75
-
-
-
3
2
66.7
Bronx
6
3
50
6
4
66.7
8
5
62.5
1
0
0
Brooklyn
7
5
71.4
9
8
88.9
4
3
75
16
14
87.5
Elmhurst
1
1
100
3
1
33.3
4
3
75
-
-
-
Flushing
3
3
100
6
4
66.7
1
1
100
3
3
100
Harlem
-
-
-
-
-
-
12
8
66.7
-
-
-
Jewish Brooklyn
6
4
66.7
15
13
86.7
12
10
83.3
20
17
85
Kings County
3
3
100
2
2
100
3
3
100
1
1
100
Lincoln
4
4
100
1
1
100
7
5
71.4
2
2
100
L. 1. Jewish
2
2
100
16
14
87.5
2
0
0
7
7
100
Mt. Sinai
3
2
66.7
6
3
50
5
5
100
7
3
42.9
New York
4
4
100
15
11
73.3
1
1
100
8
7
87.5
Queens Gen.
4
4
100
-
-
-
11
10
90.9
2
1
50
St. Vincent's (NY)
3
3
100
5
0
0
3
2
66.7
2
2
100
St. Vmcent's (SI)
3
3
100
7
6
85.7
-
-
-
-
-
-
TOTALS
67
53
79.1
103
74
71.8
78
61
78.2
74
60
81.1
Table 15. Neonatal Survival by Birth Weight (< 1000 grams)
Province of Quebec
Table 14. Deaths/1000 LIvebirths - 1966-1973
State of Oregon/United States
1966 1967 1968 1969 1970 1971
1972 1973
Neonatal Mortality
United States
Oregon
Premature Mortality
Oregon (1001-
2500 gmsl
17.2 16.2 159 15.6 15.1 14.2
15.1 13.7 143 12.0 109 11,8
115,7 101,5 106 3 83.7 87.6 97.2
13.6 13.0
11,5 10,5
86.7 72.2
Birth Weight
Number
Number
%
Number
%
(gm)
Liveborn
Survived
Survived
Stillbirths
StillbirOil
501-550
101
0
0.0
80
44,2
551-600
117
0
0.0
73
38.3
601-650
75
1
1.3
59
44.0
651-700
136
2
1.5
79
36.7
701-750
93
3
3.2
50
35.0
751-800
97
4
4,1
51
34.5
801-850
83
8
9.6
39
32.0
851-900
83
9
10.8
36
30.2
901-950
123
18
14.6
74
37.6
961-1000
103
18
17,5
54
34.3
Table 16. Referral Neonatal Intensive Care Results
for 501-1 OOOg Infants Admitted 0-24H Age
to Montreal Children's Hospital 1970-1974 Inclusive
Deaths
Survi\
ors (discha
rged alive)
Birth Weight
Number
(gml
Admissions
Number on
0 - 7 Days
Aft
er 7 Days
Number
%
Respirators
Who Survived
501-550
1
1
0
0
0
(0)
551-600
3
2
1
0
0
(0)
601-650
4
4
0
0
0
(0)
651-700
12
11
1
0
0
(0)
701-750
8
6
0
2
25
(1/2)
751-800
13
7
4
2
15
(0/2)
801-850
15
9
3
3
20
(0/3)
851-900
9
5
2
2
22
(0/2)
901-950
19
8
7
4
21
(2/4)
951-1000
20
10
2
8
40
(5/8)
Subtotals
501-750
28
24
2
2
7
(1/2)
751-1000
76
39
18
19
25
(7/19)
Total
104
63
20
21
32
(8/211
Figures courtesy Mi
ss Coll
nge
M.Sc.N.
Montrea
1 Child
en's Hospital. Quebe
These infants were
ransfe
red
from the
followin
g hospi
als. and include for p
survivors from these
hospi
als.
Livebi
ths 1970
-1974
St. Mary's
7000
Catherine Booth
Lachine General
3100
Santa Cabrini
Reddy Memorial
2000
Queen Elizabeth
Montreal General
6900
Brome Missisquoi
Bellechasse
8700
Plattsburgh, N.Y.
Lakeshore
7300
Jean Talon
Notre-Dame
9400
Saranac Lake. N.Y
Barrie Memorial
1200
Lasalle General
, Canada
actical purposes all 501-1000 gn
6600
4600
2300
5000
6800
1500
6800
TOTAL POPULATION REPRESENTED
21 Survivors 501-1000 gm/± 85,200 livebi
85,200 CONSECUTIVE LIVEBIRTHS
hs = rate of 2.5/10,000 livebirths.
Table 17. Neonatal Survival By Birth Weight
Stanford University Medical Center
Number Died
Numbe
Died
Birth Weight
Number
Gestational
Number
%
Number
Number
Gestational
Number
%
Number
(gm)
Liveborn
Age (wks)
<26 >28
Survived
Survived
Stillborn
Liveborn
Aged
<26
vks)
<28
Survived
Survived
Stillborn
1964
1965 1
Less than 500
0
0 0
0
0
7
1
1
0
0
0.0
1
501-550
1
1 0
0
0
3
2
2
-
0
0.0
1
551-600
1
1 0
0
0
2
0
-
-
-
-
0
601-650
0
0 0
-
-
0
1
1
-
0
0.0
0
651-700
0
0 0
-
-
1
0
0
-
-
_
1
701-750
0
0 0
-
-
2
0
0
-
-
-
0
751-800
0
0 0
-
-
2
0
0
-
-
-
0
801-850
1
1 0
-
-
2
0
0
-
-
-
0
851-900
1
1 0
0
0
0
1
1
-
0
0.0
0
901-950
0
0 0
-
-
0
3
2
-
1
33.3
1
951-1000
0
0 0
-
-
0
4
2
'
2
50.0
0
TOTAL
4
4 0
0
0
19
(82.6%)
12
9
-
3
7.5
4
(25%)
1966
1967
Less than 500
0
-
-
-
1
1
0
0
0.0
1
501-550
0
-
-
-
0
0
-
-
-
-
2
551-600
0
-
-
-
1
1
0
0
0.0
2
601-650
0
-
-
-
1
0
-
-
-
-
1
651-700
2
2 0
0
0
0
2
0
I
50.0
2
701-750
1
1 0
0
0
0
0
-
-
-
-
1
751-800
0
-
-
-
2
1
0
0
0.0
0
801-850
0
-
-
-
1
3
1
1
33.3
1
851-900
2
2 0
0
0
0
1
0
0
1
100.0
1
901-950
1
1 0
0
0
0
4
4
0
0
0.0
0
951-1000
0
-
-
-
0
2
1
0
1
50.0
0
TOTAL
6
6
0
0
6
(50%)
15
10
1
4
26.7
11
(42.3%)
1968
1969
Less than 500
4
4 0
0
0
1
0
0
0.0
3
501-550
0
0 0
-
-
0
0
0
0
-
-
0
551-600
0
0 0
-
-
0
0
0
0.0
1
601-650
0
0 0
-
-
0
0
0
0
-
-
0
651-700
1
1 0
0
0
0
0
0
0.0
2
701-750
0
0 0
-
-
0
0
0
0
-
-
3
751-800
0
0 0
-
-
0
0
0
0.0
0
801-850
0
0 0
-
-
1
0
0
0
-
-
0
851-900
1
1 0
0
0
1
0
0
0.0
0
901-950
1
1 0
0
0
0
3
2
0
1
33.3
0
951-1000
0
0 0
-
-
0
0
0
1
1 00.0
0
TOTAL
7
7 0
0
0
3
(17.6%)
9
7
0
2
22.2
9
(50%)
12-91
Table 17. (Continued)
Number Died
Number Died
Birth Weight
Number
Gestational
Number
%
Number
Number
Gestat
onal
Number
%
Number
(gm)
Liveborn
Age (wl<s)
<26 >28
Survived
Survived
Stillborn
Liveborn
Age(»
<26
vks)
<28
Survived
Survived
Stillborn
1970
1971
Less than 500
1
1 0
0
0.0
1
1
1
0
0
0.0
2
501-550
2
2 0
0
0.0
0
0
0
0
-
-
0
551-600
2
1 0
1
50.0
0
1
1
0
0
0.0
2
601-650
0
0 0
-
-
0
1
1
0
0
0.0
0
651-700
2
2 0
0
0.0
0
1
1
0
0
0.0
1
701-750
0
0 0
-
-
0
0
0
0
-
-
0
751-800
0
0 0
-
-
0
0
0
0
-
-
0
801-850
2
1 0
1
50.0
0
0
0
0
-
-
0
851-900
1
1 0
0
0.0
0
2
2
0
0
0.0
0
901-950
3
3 0
0
0.0
0
0
0
0
-
-
1
951-1000
4
3 1
0
0.0
0
4
1
0
3
75.0
0
TOTAL
17
14 1
2
11.8
1
(5.6%)
10
7
0
3
30.0
6
(37.5%)
1972
1973
Less than 500
2
2 0
0
0.0
1
1
1
0
0
0.0
1
501-550
0
0 0
0
0.0
0
0
0
0
-
-
1
551-600
1
1 0
0
0.0
0
0
0
0
-
-
0
601-650
2
2 0
0
0.0
0
0
0
0
-
-
0
651-700
1
0 1
0
0.0
0
0
0
0
-
-
2
701-750
1
1 0
0
0.0
1
2
2
0
0
0.0
0
751-800
0
0 0
-
-
0
2
2
0
0
0.0
0
801-850
0
0 0
-
-
0
1
1
0
0
0.0
1
851-900
0
0 0
-
-
0
0
0
0
-
-
2
901-950
2
1 0
1
50.0
1
2
1
0
1
50.0
0
951-1000
1
0 0
1
100.0
0
2
2
0
0
0.0
0
TOTAL
10
7 1
2
20.0
3
(23.1%!
10
9
0
1
10.0
7
(41.2%)
1974
Less than 500
0
0 0
^
-
3
501-500
1
1 0
0
0.0
1
551-600
1
1 0
0
0.0
0
601-650
0
0 0
-
-
0
651-700
0
0 0
-
-
0
701-750
2
2 0
0
0.0
1
751-800
0
0 0
-
-
1
801-850
1
1 0
0
0.0
2
851-900
1
1 0
0
0.0
0
901-950
0
0 0
-
-
0
951-1000
1
1 0
0
0.0
0
TOTAL
7
7 0
0
0.0
8
153.3%)
12-92
Table 18. Neonatal Survival by Birth Weight and Gestational Age
Livaborns - Birth Weights <1000 grams - 1963-1973
University of Colorado Medical Center, Denver
Birth Weight
Gestational Age (wl<s)
Total
Number
%
(gms)
24 26
28 30 32 34 36 38 Unknown
Number
Survived
Survived
7/1/63-6/30/64
Less than 450
451-500
501-550
1
1
0
0
551-600
3
3
0
0
601-650
651-700
701-750
751-800
1
1
0
0
801-850
851-900
1 .
1
0
0
901-950
2
2
1
50
951-1000
TOTAL
4 1
2 1
8
1
12.5
7/1/64-6/30/65
Less than 450
451-500
501-550
551-600
1
1
0
0
601-650
1
1
0
0
651-700
2
1
3
0
0
701-750
1
1
0
0
751-800
1
1
0
0
801-850
1
1
0
0
851-900
1
1
0
0
901-950
1
1
0
0
951-1000
2
2
1
50
TOTAL
5 4
3
12
1
8.3
7/1/65-6/30/66
Less than 450
451-500
501-550
1
1
0
0
551-600
2
2
0
0
601-650
1
1
0
0
651-700
2
2
0
0
701-750
2
2
0
0
751-800
1
1
0
0
801-850
1
1
0
0
851-900
901-950
951-1000
TOTAL
8 1
1
10
0
0
12-93
Table 18 (Continued)
Birth Weight
Gestational Age (wks)
Total
Number
%
(gms)
24 26
28 30 32 34 36 38 Unknown
Number
Survived
Survived
7/1/66-6/30/67
Less than 450
451-500
501
550
1
1
0
0
551
600
601
650
1
0
0
651
700
1
0
0
701
750
1
0
0
751
800
1
0
0
801
850
1
0
0
851
900
1
1
100
901
950
1
2
3
2
66.6
951
1000
TOTAL
4 2
4
10
3
30
7/1/67 -6/30/68
Less than 450
451-500
501
550
551
600
1
1
0
0
601
650
2
2
0
0
651
700
701
750
1
1
0
0
751
800
1
1
0
0
801
850
1 1
1
3
0
00
851
900
901
950
1
1
0
0
951
1000
TOTAL
3 3
2 1
9
0
0
7/1/68-6/30/69
Less than 450
451-500
501
550
551
600
1
1
2
0
0
601
650
1
1
2
0
0
651
700
701
750
751
800
801
850
2
2
0
0
851
900
901
950
1 1
1
3
0
0
951
1000
TOTAL
2 4
1 2
9
0
0
Table 18 (Continued)
Birth Weight
Gestational Age (wks)
Total
Number
%
(gms)
24
26 28 30 32 34 36 38 Unknown
Number
Survived
Survived
7/1/69-6/30/70
Less than 450
451-500
501
550
3
3
0
0
551
600
601
650
1
1
0
0
651
700
701
750
751
800
1
0
0
801
850
1
1 1
3
0
0
851
900
1
0
0
901
950
1
0
0
951
1000
1 1
2
0
0
TOTAL
4
6 2
12
0
0
7/1/70-6/30/71
Less than 450
451-500
501
550
551
600
601
650
2
2
0
0
651
700
1
1
0
0
701
750
1
11
3
0
0
751
800
1
1
0
0
801
850
1
1
2
0
0
851
900
901
950
1
1
0
0
951
1000
1
1
TOTAL
5
4 1 1
11
0
0
7/1/71 -6/30/72
Less than 450
451-500
501
550
551
600
601
650
651
700
701
750
2
2
0
0
751
800
1
1
0
0
801
850
851
900
1
1
2
0
0
901
950
1
4 1
6
0
0
951
1000
TOTAL
3
7 1
11
0
0
12-95
Table 18 (Continued)
Birth Weight
Gestational Age (wks)
Total
Number
(qms)
24
26 28 30 32 34 36 38 Unknown
Number
Survived
Survived
7/1/72-6/30/73
Less than 450
451-500
501
550
551
600
601
650
1
2
0
0
651
700
701
750
751
800
1
1
2
0
0
801
850
1
1
0
0
851
900
1
1
2
0
0
901
950
1
1
2
1
50
951
1000
TOTAL
3
2
2 1
9
1
111
Table 19. Neonatal Survival by Birth Weight
Birth Weights < 1000 Grams - 1963-1973
Boston Hospital for Women
Birth Weight
(gm)
Number
Livebirths
Number
Survived
28 Days
%
Survival
Number
Fetal
Deaths
%
Fetal
Deaths
<500
33
0
0.0
93
73.8
501-550
12
0
0.0
19
61.3
551-600
25
0
0.0
16
39.0
601-650
20
1
5.0
15
42.8
651-700
31
2
6.4
21
40.4
701-750
28
2
7.1
14
33.3
751-800
28
1
3.6
15
34.9
801-850
18
3
16.6
12
40.0
851-900
26
3
11.5
12
31.6
901-950
41
6
14.6
8
16.3
951-1000
Total
31
13
41.9
15
32.6
293
31
10.6
240
45.0
12-96
Table 20. Neonatal Survival by Birth Weight and Gestational Age
Liveborns - Birth Weighte <1000 Grams - 1970-1974
University of Minnesota Medical Center, Minneapolis — Neonatal I. C. U.
Birth Weights
Gestational Age (wks)
Total
Number
%
(gms)
24
26 28 30 32 34 36 38 Unknown
Number
Survived
Survived
1970
Less than 450
451-500
1
1
0
0
501
550
551
600
1
1
0
0
601
650
651
700
701
750
2
2
0
0
751
800
801
850
1
1
0
0
851
900
1
1
1
3
0
0
901
950
1
1
1
100
951
1000
2
2
0
0
TOTAL
3
2
2 3
1
11
1
9.1
1971
Less than 450
451-500
1
1
0
0
501
550
551
600
1
1
0
0
601
650
651
700
1
1
0
0
701
750
1
1
0
0
751
800
1
1
2
0
0
801
850
851
900
2
2
2
100
901
950
1
1
2
0
0
951
1000
TOTAL
3
3
2 2
10
2
20
1972
Less than 450
451-500
1
1
0
0
501
■550
1
1
0
0
551
-600
1
1
0
0
601
650
2
2
0
0
651
700
701
750
1
1
2
0
0
751
800
1
1
2(26-30)
4
1
25
801
850
1
1
2 (28-29)
4
2
50
851
900
1
1
1 (24-28)
3
0
0
901
950
1 1
2
1
50
951
1000
3
3
0
0
TOTAL
4
5
7 2
5
23
4
17.4
Table 20 (Continued)
Birth Weights
Gestationa
Age (wks)
Total
Number
%
(gms)
24 26
28
30 32
34 36 38 Unknown
Number
Survived
Survived
1973
Less than 450
451-500
501
550
551
600
601
650
1
1
0
0
651
700
1
1
0
0
701
750
1
1
0
0
751
800
3
3
0
0
801
850
851
900
1
1
2(25-33)
4
0
0
901
950
1
1
3(23-32)
5
1
20
951
1000
1
1
5(27-33)
7
1
14.3
TOTAL
2 6
1
3
10
22
2
9.1
1974
Less than 450
451-500
501
550
551
600
1
1
0
0
601
650
651
700
701
750
1
1
0
0
751
800
1
1
0
0
801
850
2
2
0
0
851
900
1 1
1
3
0
0
901
950
951
1000
1
1
2
0
0
TOTAL
2 4
4
10
0
0
12-98
Table 21. Neonatal Survival by Birth Weight and Rate of Stillborns by Birth Weight
Birth Woighu < 1000 Grams - 1973-1974
Cincinnati General Hospital
LIVEBORN:
Weight (gms)
1973
1974
Total
Survived
Total
Survived
0-250
251-500
3
7
501-550
4
1
1
551-600
3
1
2
601-650
4
3
651-700
2
701-750
3
3
751-800
3
801-850
2
1
6
851-900
2
, 3
1
901-950
2
1
3
951-1000
4
3
2
Combined Survivors Two Years = 7/63 =
11%
STILLBORN:
500-550
2
551-600
3
601-650
3
651-700
701-750
3
2
751-800
1
801-850
1
851-900
1
1
901-950
1
951-1000
3
1
THERAPEUTIC ABORTIONS:
1973
1974
N=33
N=50
No weights available.
12-99
Table 22. Neonatal Survival by Birth Weight and Gestational Age
Liveborns - Birth Weights < 1000 grams - 1965-1974
University of California, San Francisco — Totals (Inborn and Outborn)
1965
Birth Weight
Gestational Age (wks)
Total
Number
%
(gms)
24 26 28 30 32 34 36 38 Unknown
Number
Survived
Survived
Less than 450
451-500
501
550
551
600
601
650
651
700
1
1
0
0
701
750
751
800
1
1
1
100
801
850
851
900
1
1
0
0
901
950
1
1
2
0
0
951
1000
1
1
0
0
TOTAL
5
6
1
16.7
1966
Less than 450
451-500
1
1
0
0
501
550
551
600
1 1
2
0
0
601
650
651
700
1
1
0
0
701
750
751
800
801
850
851
900
1
0
0
901
950
1
1
1
100
951
1000
2
3
1
33.3
TOTAL
2
* 3
9
2
22.2
1967
Less than 450
451-500
1
1
0
0
501
550
551
600
601
650
1 1
2
0
0
651
700
701
750
751
800
2
2
1
50
801
850
1
1
0
0
851
900
1
1
0
0
901
950
951
1000
1
1
100
TOTAL
5 3
8
2
25
12-100
Table 22 (Continued)
1968
Birth Weight
Gestational Age (wks)
Total
Number
%
(gms)
24 26 28 30 32 34 36 38 Unknown
Number
Survived
Survived
Less than 450
451-500
501-550
551-600
601-650
1
1
0
0
651-700
1
1
0
0
701-750
751-800
1 1
2
0
0
801-850
1 1 2
4
1
25
851-900
3 1
4
2
50
901-950
1 1 1
3
1
33.3
951-1000
1 1
2
1
50
TOTAL
2 6 4 3 1 1
17
5
29.4
1969
Less than 450
451-500
501-550
551-600
601-650
1
1
0
0
651-700
1
1
0
0
701-750
1 1
2
0
0
751-800
801-850
851-900
1
1
1
100
901-950
11
2
1
50
951-1000
1 1
2
2
100
TOTAL
3 3 12
9
4
44.4
1970
Less than 450
451-500
501-550
551-600
601-650
1
1
0
0
651-700
701-750
751-800
801-850
851-900
2
2
1
50
901-950
1
1
0
0
951-1000
TOTAL
1 1 2
4
1
25
12-101
Table 22 (Continued)
1971
Birth Weight
Gestational Age (wks)
Total
Number
%
(gms)
24 26
28 30 32 34 36 38 Unknown
Nunnber
Survived
Survived
Less than 450
451-500
501
550
551
600
601
650
651
700
701
750
1
1
2
0
0
751
800
801
850
1
1
0
0
851
900
2
2
0
0
901
950
1
1
0
0
951
1000
1
1
0
0
TOTAL
2
5
7
0
0
1972
Less than 450
451-500
501
550
551
600
601
650
1
1
0
0
651
700
1
1
0
0
701
750
751
800
1
1
0
0
801
850
1 1
2
1
50
851
900
901
950
2
1 1
4
1
25
951
1000
1
1
2
1
50
TOTAL
6
3 2
11
3
27.3
1973
Less than 450
451-500
501
550
551
600
1
1
0
0
601
650
3
3
1
33.3
651
700
1
1
0
0
701
750
1
1
0
0
751
800
1 1
2
4
1
25
801
850
1
1
0
0
851
900
901
950
2
1 1
4
2
50
951
1000
1
1 1 2
5
1
20
TOTAL
3 9
4 1 1
20
5
25
12-102
Table 22 (Continued)
1974
Birth Weight
Gestational Age (wks)
Total
Number
%
(gms)
24
26
28
30 32 34 36 38
Unknown
Number
Survived
Survived
Less than 450
451-500
1
1
0
0
501
550
1
0
0
551
600
1
0
0
601
650
1
0
0
651
700
1
2
0
0
701
750
1
2
0
0
751
800
3
2
1
7
2
28.6
801
850
1
1
0
0
851
900
1
1
2
0
0
901
950
3
2
1
6
6
66.7
951-1000
1
1
3
5
2
40
TOTAL
7
6
7
3
6
29
8
27.6
Table 23. Neonatal Survival by Birth Weight
Birth Weights < 1000 Grams - 1974
University of Arizona, Tucson
2 Hospitals
University Hospital - # 9 < 1000 gms
Live Births - 9000
Tucson Medical Center - # 17 <1000 gms
UNIVERSITY HOSPITAL
TUCSON MEDICAL CENTER
TOTAL
Birth
Number %
Number %
Number
%
Weight
Number Survived Survived
Number Survived Survived
Number
Survived
Survived
Under 500
0 - -
0 - -
0
_
_
501-550
0 - -
0 - -
0
-
-
551
600
0 - -
0 - -
0
-
-
601
651
0 - -
1 0 0
1
0
0
651
700
0 - -
3 1 33.3
3
1
33.3
701
750
0 - -
3 0 0
3
0
0
751
800
1 0 0
0 - -
1
0
0
801
850
3 0 0
0 - -
3
0
0
851
900
3 2 66.7
2 2 100
5
4
80
901
950
1 1 100
3 1 33.3
4
2
50
951
1000
1 0 0
5 2 40
6
2
33.3
-
. .
^
=
=
TOTAL
9 3 33.3
17 6 35.3
26
9
34.6
Table 24. Neonatal Survival by
Gestational Age - 1966-1974
Royal Victoria Hospital
Montreal, Quebec, Canada
Table 25. Neonatal Survival by
Gestational Age - 1964 1974
Royal Victoria Hospital, Montreal
University of California, San Francisco
University of Colorado
Gestational
Age
(wks)
Number
Livebirths
Over 500 gm
%
Survival
% Survival
Excluding Deaths
from Malformation.
Hydrops
20
1
0.0
0.0
21
5
0.0
0.0
22
8
0.0
0.0
23
5
0.0
0.0
24
14
0.0
0.0
25
23
8.7
9.0
26
41
19.4
20.5
27
33
51.5
54.8
28
25
76.0
76.0
29
44
70.4
77.6
30
51
78.4
83.3
31
67
88.1
90.8
32
70
91.4
97.0
Gestational Age
(wks)
Number
Livebirths
N
Su
umber
%
Survivors
Less than
24
31
0
0.0
24
58
0
0.0
25
43
3
6.9
26
82
13
15.8
27
54
23
42.5
28
67
31
46.2
29
50
32
64.0
30
63
45
71.4
31
71
61
85.9
32
72
65
90.2
Table 26. Survival Rates of 501-1000 Gram Livebirths
1920 - 1974
With Neonatal Intensive Care in Maternity Hospital of Birth
Birth Weight
(gms)
1920
Finland*
30 days
%
1955-1957
New York City**
7 days 28 days
% %
1966-1970
R.V.H.***
Discharged
7 days Alive
% %
1971-1974
R.V.H.***
Discharged
7 days Alive
% %
501-750
751-1000
10
0 0
11 9
3 3
28 16
11 4
61 35
*Yllpo*s experience in Finland, published in Hess, Premature and CongenitaHy diseased infants. Lea &
Feblger, Philadelphia and New York. 1922, p. 375. (for infants 600-1000 gm).
•For white infants receiving intramural care in hospital of birth, in 10 premature Centers, New York City,
In Silverman, W.A., Premature infants, E. C.Dunham, Editor, Third Edition, New York, Paul B. Hoeber,
Inc., 1961, PP. 484-487.
* Royal Victoria Hospital, Montreal.
Q
^
£
1
<
■o
■o
c
r
cu
a
OQ
o
o
>
I
o'
a>
S
nr
t5
3
n
S
r
>
0
a
>
o
o
<
cc
o
ANTENATAL
REFERRALS
1971-1974
S/B L/B N/D
'"-'-- "•"'^RSS;
=
1974
S/B L/B N/D
::-""- /t:!!
ts
1973
S/B L/B N/D
... .... ..... g
s
1972
S/B L/B N/D
/;/ ----:-::!
a
1971
S/B L/B N/D
. . » R =0 g
-
1970
S/B L/B N/D
1
1 1
2 1
2 1
2 1
2 5 4
3 11 3
2 32 2
3 106
6 2079 5
s
1969
S/B L/B N/D
::~:/ '-EE
=
1968
S/B L/B N/D
2 2
3 2
1 1
2
2 2
2 2 1
1 2 2
2 7 1
3 12 4
5 39 7
6 132 1
9 2519 5
s
1967
S/B L/B N/D
1 3 3
2 3 3
2 1 1
2 3 3
3 3
1 1 1
1 12 3
3 7 1
5 47 3
5 131 6
19 2550 10
s
1966
S/B L/B N/D'
1 2 2
2 1 1
1
1 2 2
2
1 1 1
1 1
1 8 6
2 2
5 8 3
4 9 2
3 45 4
6 161 5
19 2976 14
Incidence LBW
Livebirths/1000
501-2500/Total>500 75
550
-600
-650
-700
750
800
-850
900
950
-1000
-1250
-1500
-2000
-2500
2500
SffiSSSSSSgS§Sg§|
Table 28. Fetal Deaths - 1966-1973
Los Angeles County-University of
Southern California Medical Center
Year
Alive on
Admission
to Delivery
Service
Fetal Deaths
Fetal Death
Rate/1000
Number
Patients
Monitored
% Patients
Monitored
1966-69
1970
1971
1972
1973
37,013
9,654
9,303
9,318
10,319
804
157
155
137
136
23
16
16
15
13
1,798
2,337
2,828
3,329
0
18
15
30
32
Table 29. Intrapartum Fetal Deaths -
1970-1973
Los Angeles County-University of
Southern California Medical Center
Monitored
Unmonitored
Total patients
Fetal deaths
Rate/1000
9,871
15
1.5
28,722
108
3.7
Table 30. Fetal Mortality - 1968-1972
Parkland Hospital, University of Texas Southwestern Medical School
Fetal Death
Neonatal Death
Year
Live Births
Fetal Deaths
Rate/1000
Rate/ 1000
1968
5,955
126
21
23
1969
6,347
122
19
24
1970
6,779
142
21
18
1971
6,939
127
18
15
1972
6,772
124
18
16
Table 31. Neonatal Survival - 1970-1973
Los Angeles County /University of
Southern California Fetal Monitoring
Monitored
Unmonitored
<1500 granns
Live Births
112
448
Neonatal Survivals
60
183
Survival %
54
40.8
1000-1500 grams
Live Births
82
279
Neonatal Survivals
53
161
Survival %
64.6
57.7%
< 1000 grams
Live Births
30
169
Neonatal Survivals
7
22
Survival %
23.3
13.0
Table 32. Neonatal Mortality - 1966-1973
Deaths/1000
LAC-USC*
University of Oregon
1966-69
26
19.4
1970
18
11.0
1971
15
14.2
1972
12
9.8
1973
9.5
10.1
•Los Angeies County/Unluersity of Southern Call
Table 33. Neonatal Survival by Birth Weight and Gestational Age - 1958-1968 and 1971-1973
Denver Children's Hospital
Number
Number
%
Gestational Age Birth Weight
Live Births
Survived
Survived
1958-1968
< 30wks <1000gms(%SGA)
89
7
8
<30wl<s 1000-1500
77
29
37.7
30-34 wks 1 000-1 500 (% SGA)
70
44
62.9
30-34 wks 1 500-2000
154
124
80.5
34-38 wks 2000-2500
523
506
96.7
SJ.
=
:
TOTAL
913
710
77.8
1971-1973
<30wks <1000gms(y2SGA)
28
1
3.6
< 30 wks 1000-1500
27
11
40.7
30-34 wks 1000-15001% SGA)
22
15
68.2
30-34 wks 1 500-2000
48
43
89.6
34-38 wks 2000-2500
231
224
96.9
TOTAL
356
294
82.6
Table 34. Neonatal Survival by Birth Weight - 1965-1974
University of California at San Francisco
Changes in Survival (%)
1965- 1989
1970-
1974
Birth Weight
Number Liveborn % Surviving
Number Liveborn
% Surviving
901-950
6 17
8
50
951-1000
6 50
4
75
1001-1250
30 57
32
66
1251-1500
35 66
42
83
1501-2000
151 90
120
94
2001-2500
493 92
441
99
> 2500
9,110 99.6
6,879
99.7
Table 35. Distribution of Livebirths by Weight Group/1000 Livebirths
Royal Victoria Hospital, Montreal, Quebec
1971-1974
1966-1970
(Excluding Antenatal
Referrals & Abortions
501-750
30/13320
2.25
21/8487
2.47
751-1000
42/13320
3.15
19/8487
2.24
1001-1250
43/13320
3.23
13/8487
1.53
1251-1500
51/13320
3.83
30/8487
3.53
1501-2000
196/13320
14.7
109/8487
12.8
2001-2500
643/13320
48.3
358/8487
42.2
Over 2500
12315/13320
924.5
7937/8487
935.2
Subtotals
501-1000
72/13320
5.4
40/8487
4.7
1001-2500
933/13320
70.0
510/8487
60.1
Liberalised abortion began in 1971.
APPENDIX C
Table 36. Data Collection Form
Please check appropriate year when procedure was started: (1964- 1974)
Obstetrical Improvements
1. Antenatal high risk clinic
2. Amniocentesis
bilirubinoid pigment
chromosomal anomalies
sex determination
inborn errors of metabolism
intrauterine transfusion
fetal maturity - L/S ratios
bilirubin
creatinine
3. Sonography- anomalies
fetal maturity
placental localization
5. Other evaluations of fetal well being
maternal urine - E3, estriol
maternal blood - human plasma lactogen
fetoprotein
contraction stress test
6. Beta methasone for lung maturation
7. Drugs to arrest premature labor:
MgS04
alcohol
Beta sympathomimetic
8. Fetal monitoring
Heart rate & uterine pressure activity
Beat-to-beat analysis of HR
Evaluation of pre-ejection phase (EKG and HR)
Monitoring of fetal respirations
Fetal EEG
Fetal scalp ph
Resuscitation in delivery room
Better trained personnel - nurses
neonatal fellow/s at
problem deliveries
Thermal regulation
More aggressive intubation & suctioning
Umbilical artery & vein acid base
Correction of acidosis
Transitional nursery on the delivery floor
Observation
Stabilization of ill nevi/borns
Neonatal Intensive Care Unit
64
69-70
69-70
69-70
63-67
70-71
67
6&-66
72
72
72
4. Amnioscopy - color of amniotic fluid and vernix 73-73
65-70
72
73
73
73
64
68-69
73
70-71
72
74
65
68-73
66
69
69
69
12-109
Table 36. (Continued)
Transport System 70
Regionalization of Newborn Care 70-71
Personnel;
1. Specially trained nurses 65
2. Neonatal fellows 65
3. Anesthesiologist 69-70
4. Respirator tecfiniclans 71
Equipment: with alarm systems
Continual oxygen monitors 68-69
Apnea monitors 66-68
Heart rate monitors 66-68
Humidity monitors 70-72
Thermal monitors (thermidor probes) 67
Blood pressure monitors: Doppler 72
Ultra sound
Transducers for direct arterial blood pressure
measurements 70-72
Improved ambu bags (> 40% ©2 ) 66
Microchemistries:
Arterial & capillary blood gas monitoring 64
Electrolytes 64
Ca, glucose, Mg 64
Bilirubin 64
Bilirubin binding . 71
Total proteins 64
Alb/glob 64
Protein electrophoresis 64
Hematology studies: routine 64
Coagulation studies 69-70
G6PD 69-70
Liver chemistries 64
Coombs, type & crossmatch 64
Viral studies
Metabolic disease screening 68
Procedures;
Early feeding (note 4, 6, 12 or 24) 69-70
Umbilical artery catheterization for blood sampling 69
Radial & temporal arterial punctures or cath
monitoring for oxygenation 69
Mechanical ventilation 68
PEEP (positive end expiratory pressure) 70-71
CPAP (continuous positive airway head box) 72
nasal prongs 74
Negative pressure vent
Phototherapy - intermittent 68-69
continuous 68-69
Intravenous hyperalimentation 70
IMasojejunal feeding 73-74
68
12-110
Table 36. (Continued)
Cardiac catheterization techniques 65
Cardiac surgery 64
Aggressive gastrointestinal surgery 64
Evaluation of gestational age: 64
pE 69
Neurological exam 70
Nerve conduction time ■ ■ . 70
EEG
Antibiotics:
Ampicillin 69
Kanamycin 65
Gentamycin 70-1
Penicillinase resistant antibiotics 65
Routine monitoring of Hct & Hb electrolytes, 6&-66
dextrostix & glucose, Ca
ICU Nurses:
1. specially trained 64-65
2. Umb cath care & blood drawing 69-70
3. Dextrostix monitoring 70
4. oro-nasotracheal care 70
5. Ambuing 65
6. heelstick blood drawing (except type & cross) 70
7. starting peripheral IV's
Treatment Improvements:
Anesthesia
Post-op care
Surgical techniques
Resuscitation
RDS, meconium aspiration
Hypoglycemia
Hypocalcemia
Polycythemia
Coagulation defects
Sepsis Rx
Erythroblastosis fetalis
Metabolic disorders
Drug doses
Environmental stimulation
12-111
Case Reports of Infants Who Survived at Birth Weights Less
Than 601 Grams or Gestational Ages of 24 Weeks or Less
Case Report 1
UNIVERSITY OF CINCINNATI MEDICAL CENTER DOB: 9/3/73
This was a 580-gram black female infant born by breech extraction with
prolapsed cord on 9/3/73 with estimated gestational age of 25-27 weeks. The
Apgars were 5 and 8 at 1 and 5 minutes, respectively. On physical examination
the newborn appeared to be between 24-25 weeks of gestation with no abnormal
physical findings. Shortly after birth the infant developed severe respiratory
distress with possible sepsis. An umbilical artery catheter was placed to moni-
tor blood gases which was found by x-ray later to be free in the peritoneum.
In addition to respiratory distress the newborn experienced several episodes of
apnea and bradycardia during the first three days of life. These were treated
by frequent "ambuing." Additional problems concerning this infant were: (1)
Anemia, which required two transfusions. (2) Nutrition: on day 5 nasogastric
tube was passed by continuous gavage feedings. In addition, aminosol was given
by peripheral intravenous drip. These modes were continued for three weeks when
gavage feedings were begun at every 3-hour interval. (3) Phototherapy was used
for several days to prevent hyperbilirubinemia. The highest bilirubin recorded
was 4.5 milligram percent.
The infant was discharged at three months of age with a weight of 2270
grams; head circumference, chest circumference and length were all below the
tenth percentile. On follow-up visit at 17 months of age the neurological exam
is within normal limits. Her size is still small. She's just walking now and
has a vocabulary of about ten words, but it is felt by the examining physician
that she is slow in her development.
Case Report 2
UNIVERSITY OF MARYLAND HOSPITAL DOB: 11/17/72
This is a 539-gram black female infant born to a 29-year-old gravida 5,
para 5, A-positive, VDRL-negative mother with approximate gestational age of
28 weeks. The Apgars were 0 at 1 minute and 4 at 5 minutes. The physical exam
revealed a small immature female infant with head circumference of 21 cm, chest
circumference of 18 cm, length of 31 cm, and no abnormal findings.
Hospital course: At two hours of age an umbilical artery catheter was
passed and arterial blood gasses were obtained; pH was 7.21; PCO2 was 45; p02
was 34; BE was -10; HCO3 was 17.5. The infant was placed in 50 percent oxygen
12-112
and given bicarbonate. The following day oxygen was lowered to 40 percent
and by day 3 she no longer required any oxygen.
On day 2 phototherapy was begun to prevent hyperbilirubinemia and was
continued for several days. Oral feedings of 1 cc every two hours by gavage
were begun on day 3 when the weight of the infant was only 482 grams. Another
problem was persistent metabolic acidosis which was treated with frequent sodium
bicarbonate, given either intravenously or by mouth. This persisted for about
two weeks. On day 13 of life, episodes of apnea occurred and this continued
for another two weeks. At this same time there was a henatocrit drop of 5 points
and hypernatremia. A sepsis workup was done. The infant's weight gain was
acceptable but the head circiimference appeared to grow too rapidly in the first
two months of life, but by the third month it was proportional to the other param-
eters of weight and length. At about 3 months of age the infant was discharged
v/ith a weight of 2693 grams, with a head circumference of 33-1/2 cm, a length of
14-1/4 inches, and a hematocrit of 34. Physical examination revealed a bilater-
ally flattened head with separated sutures; eyes were normal; the rest of the
physical, including neurological, exam was normal at discharge. The infant was
again seen at 11 months when the weight was 7144 grams and length was 27 inches.
No abnormal nuerological findings were noted. At 2 years of age she was again
seen and was thought to be normal neurologically and developmental ly.
Case Report 3 ,
_ ■- UNIVERSITY OF ARIZONA AT TUCSON DOB: 12/30/74
This is a 624-gram, 24-week gestation, female infant born to a para 3,
gravida 1, abortion 2 mother with a bicornuate uterus. The Apgars were good at
birth and the physical exam was normal except for extreme immaturity. At age
1-1/2 days she developed episodes of apnea and over-per fusion of the lungs due
to a patent ductus arteriosus. Hasal CPAP was begun with no improvement in her
condition and she vjas placed on mechanical ventilation with high oxygen concen-
tration. Two days after ventilation was started because of worsening of her
condition due to severe pulmonary edema secondary to congestive heart failure,
she was taken to surgery and the PDA was ligated. After surgery the lungs
cleared and she only required 25 percent oxygen and intermittent mechanical ven-
tilation for two weeks, mainly for apnea. During this period she received intra-
venous hyperalimentation by peripheral IV. She did well until 2-1/2 months of
age, having been gavage fed with progestamil and off the ventilator and oxygen,
when she developed abdominal distention and hematest-positive stools. The diag-
nosis by x-ray was necrotizing enterocolitis with air in the portal system, for
which she is still being treated with IV hyperalimentation. The lowest weight
recorded in this infant was 500 gm on the seventh day of life. She now weighs
600 gm.
Case Report 4
Case Record: E.H. Date of Birth: 1/11 /I A
Date of Discharge: 9/23/74
This 580-gram female infant who was 29 weeks by obstetrical estimate was
admitted to Colorado General Hospital on 7/17/74 having been transferred from
Weld County Hospital in Greeley, Colorado, where she had been delivered at
7:00 p.m. on that day of cesarean section. Her mother is a 27-year-old gravida
I, para 0 woman without previous medical illness. Her pregnancy had been uncom-
plicated until 25 weeks when she developed ankle swelling which was treated with
hydrodiuril. Despite the diuretic therapy, her edema persisted; and on 7/12/74
she was found to have elevated blood pressure which was treated with hydrodiuril
and Serpasil. On the day prior to delivery the mother was found to have
increased edema, proteinuria, and hypertension and was, therefore, admitted to
the hospital. During two days in the hospital she had increasing symptoms with
hyperref lexia and jitter iness and blood pressure determinations to as high as
240/160. She was treated with Valium, phenobarbital , Diazoxide, Lasix, Apresoline,
Serpasil, and magnesium sulfate. By the evening of 7/17 it was elected to ter-
minate the pregnancy for maternal indications , as she had not yet responded to
medical management of her hypertensive disease.
Essentially it was planned to do a hysterotomy termination of the pregnancy
which was done under Flouthane , nitrous oxide, Vistaril, and atropine. The infant
was resuscitated immediately after delivery and had Apgars of 3 at 1 minute and
8 at 5 minutes. She required positive pressure resuscitation via an endotracheal
tube, was given oxygen from the first three to five minutes of life; and at this
time the child breathed spontaneously and was able to be extubated. Initial
gases in an F:02 of 45 percent showed a p02 of 229, a pC02 of 39, and a pH of
7.30. Her dextrostix was satisfactory and she was begun on an infusion via an
umbilical artery catheter of DlOW at 2 cc/hour. Arrangements for transfer to
Colorado General Hospital were promptly made and the child arrived here at approx-
imately 3 hours of age. On physical examination here the child's weight was
580 grams, her length was 34 cm, blood pressure was 62 systolic, temperature was
35.8 axillary, pulse was 150, respiratory rate was 54, and head circumference
was 24 cm. The child was incredibly small, but pink, an active newborn without
significant clinical respiratory distress. General physical examination was
completely within normal limits. Gestational age assessment by physical criteria
gave a gestational age of approximately 33 to 34 weeks, by neurological assess-
ment the gestational age was estimated between 30 and 32 weeks; therefore, an
overall clinical assessment of gestational age averaged 32 to 33 weeks. The
child's entire hosptial course was remarkably benign. She slowly tolerated the
introduction to PM-60/40 feedings and had only mild to moderate apnea responding
to stimulation over her first week in the hospital. She initially required feed-
ing by constant intragastric drip but by the end of two weeks was able to move
to intermittent gavage feeding schedule. She demonstrated steady weight gain so
that at the end of two weeks in the hospital her weight was up to 840 grams.
The remainder of her hospital course was completely benign with the only problems
12-114
being that of caloric intake and weight gain which continued smoothly. At the
time of discharge on 9/23/74, her weight was up to 1940 grams,- her general physi-
cal and neurological examination were completely within normal limits; and on
follow-up examinations in the last four months , she has continued to be a thriving
healthy vigorous child, who is a delight to her family.
This interesting child demonstrates not only viability at under 500 grams
but also the fact that severe intrauterine growth retardation may occur in
infants of this birth weight; thus, not all extremely low birth v/eight infants
can be guaranteed to be immature. The valuation of this infant for other poten-
tial causes of intrauterine growth retardation including metabolic diseases and
congenital infections was completely normal, and it is presumed that the etiology
of her growth retardation was the maternal hypertensive disease.
Case Report 5
A PREMATURE INFANT WEIGHING LESS THAN ONE POUND
AT BIRTH WHO SURVIVED AND DEVELOPED NORMALLY DOB: 5/6/37
Baby McG. was born about 10:30 p.m., on June 6, 1937, fifteen minutes
after my arrival. The child was the third born to the mother ,. who was 28 years
of age at the time. The birth was approximately two months premature. The
delivery was normal. The child was alive but so extremely small that I did not
expect survival, since there was no inciibator available. The nurse bathed the
baby in warm olive oil, wrapped it in cotton, and placed it in a basket in a
warm oven. No scales were at hand, so the actual birth weight V7as not obtained,,
but it was by far the smallest living baby I had ever seen. Shortly after birth
the nurse gave the baby two drops of brandy in warm water from an eye dropper.
Greatly to my surprise the nurse called me on the telephone the following morn-
ing to inform me that the infant was still alive and to request feeding instruc-
tions. About 11 a.m., June 7th, the day following birth, the nurse took the
baby to a local grocery store, and weighed him on the grocery scales in the pre-
sence of the proprietor and another person. The weight of the baby at that time
was 14 ounces, as the accompanying affidavit confirms. For two days the child
was given feedings of two drops of brandy and a few drops of corn syrup in warm
water from a dropper. On the third day the child was given lactogen, in a dilu-
tion of one teaspoonful to one ounce of water, and since that time has been fed
lactogen in the full strength dilution (1 part lactogen to 7 parts water) , with
progressive increases in volume as the baby grew older. For the first ten days
of life the child took several droppers of formula each hour. At ten days on
the infant was able to suck, and, therefore, ivas fed from a bottle on a two-
hour schedule. During the first two weeks che baby was kept in a warm oven at
night .
The weight at 2 months was 3 pounds, at 4 months 6 pounds, at 7 months
9-3/4 pounds, at which time the body length was 24-1/4 inches. The child has
been generally healthy and normal as to its physical and mental condition.
12-115
Cereal, vegetable puree, and other usual additions were made to the diet at
6 months.
At present the child is 12 months old, weighs 13 pounds 12 ounces, and
measures 25-1/4 inches.
J.S. Monro, North Sydney, N . S.
Canadian Medical Association Journal 40:69-70, 1939
NOTE: Dr. Behrman included the following case reports
in Appendix C:
• "Case Reports," The Canadian Association Journal 40:69-70,
January 1939.
• Lelek, K. , Limanowski, J., and Hager-Malecka, B., "A Three-Month
Old Infant With a Birthweight of 450 Grams," Pediatria Polska,
1973, T. XLVIII, 2, (in Polish).
12-116
13
THE LAW RELATING TO EXPER'IVIENTATiON
WITH THE FETUS
A. M. Capron, LL.B.
CAPRON, LL.B.
Dr. Capron is presently Associate Professor at the
University of Pennsylvania Law School.
PD304119-5(15)
The Law Relating to Experimentation
with the Fetus
1. The dead fetus (including tissues, fluids and other products of con-
ception) may be used ex utero for research with the permission of either parent,
provided that the other does not present an objection, under the terms of the
Uniform Anatomical Gift Act; the only exceptions are those imposed by recent
statutes in five states, which limit experimentation on an induced abortus to
pathological examinations or the like (three states) or which require maternal
(as opposed to paternal) consent (two states) . Grave robbing statutes do not
restrict experimentation if permission has been obtained under the UAGA. For
research involving a dead fetus in utero, the consent of the pregnant woman
should be sufficient. Caution and ignorance both suggest that the definition
of "dead" fetus should for the moment be one which is "lifeless" (in the sense
of having no signs of life, or at least no heartbeat); research with fetuses
that have other signs of life although no possibility of "recovery" should fall
into the category of experimentation on the "nonviable fetus."
2. The viable fetus ex utero is a person in the eyes of the law, and its
interest in life and well-being are clearly recognised by the civil and criminal
law. Under the common law, this protection begins when the fetus is expelled or
extracted from its mother, but at least one state has extended the criminal law
protection to the point when birth begins and the common law recognized that a
physician's duties of care commence at this point. Parents, or other guardians,
may consent to beneficial experiments for such fetuses, and with proper safe-
guards may be able to give permission for riskless studies of scientific merit,
although this point is not definitely settled in decisional law. The disquali-
fication of the mother (and perhaps the father) of an aborted fetus to act as
its guardian which is a feature of a number of recent statutes may affect fetal
research. Such attempts to take away parental custody and control on the grounds
that the mother has abandoned the fetus or is unable to take account of its
interests seem unwise (because of the burden placed on state officials which they
are ill-equipped to handle) , misguided (because it is based on misapprehension of
the significance of the decision to abort) , unnecessary (because the interests of
such fetuses are already protected by the law from parental abuse to the same
degree as those of other children) , and perhaps unconstitutional (because it
chills exercise of the right to have an abortion and operates arbitrarily through
presumptions rather than actual facts about parental choices) .
3. The viable fetus in utero does not enjoy full protection, but the law
does try to avoid prenatal injuries which will handicap or kill a person after
birth; additionally, some jurisdictions have extended their notion of fetal
interests to recognize a right for its relatives and in some cases for its
estate to sue for injuries to a viable fetus causing stillbirth. The limita-
tion on these interests is, of course, the mother's right to an abortion neces-
sary to protect her life or health even when that threatens the life or health
of a viable fetus. This would not preclude the state from protecting the viable
fetus in utero from possibly harmful experiments not connected with benefits to
the mother's health or well-being or arising without her consent.
4. The nonviable fetus ex utero has received the same respect and concern
from the law as a viable fetus in the same position, although (in the absence of
a statute directing otherwise) only normal sustenance and the prevention of pain
but not heroic "lifesaving" attempts are required in caring for it. The reasons
why "birth" was chosen as the point to begin full legal protection, even for the
nonviable, may not apply to fetal research under careful supervision and with
great attention paid to the determination of "nonviability" ; thus a redefinition
of the rights of the nonviable is conceivable. The question whether research of
this type ought to be permitted is not a legal question, however, but a policy
judgment to be reached on the basis of one's perception of the relative impor-
tance of the interests of the fetus, parents and society. If experimentation
is limited to that which is intended to benefit the fetus or pose no harm, the
authority to consent can be left with the parents as it is for viable fetuses.
Were a wider scope of experimentation to be permitted, it would seem advisable
to have outside review, which could inquire broadly into the parental decision
to permit a fetus to participate or more narrowly into only whether the estab-
lished criteria (on nonviability and the degree of risk and pain) have been met.
5. The nonviable fetus in utero has generally not been protected by the
criminal law, except to the extent that injuries received antenatally are mani-
fest after birth; the law of torts and property also regards birth as a neces-
sary precondition for rights to vest in the previable fetus. This seems to
manifest an understandable societal concern that persons not be burdened with
prenatally imposed injuries, but the pregnant woman's right to a subsequent
abortion presents an impediment to the clear authority otherwise passed by
equity to intervene so as to prevent such irreparable harm befalling (potential)
people. Any in utero research will require the woman's consent on her own
behalf; the law seems to suggest, but does not demand, that someone also consent
on behalf of the fetus. To locate the authority with the pregnant woman may be
seen as creating a conflict of interest, yet to place it with someone else who
could prevent her from participating would probably amount to an unconstitutional
infringement on her right of privacy.
I. INTRODUCTION
This memorandum will address itself primarily to the two major questions
on which the law can make a contribution to the discussion of the limits and
conditions of fetal experimentation:
1. Which interests of the fetus are protected at what points in
its development against which interests of other parties?
2. Since the fetus is unable to protect its interests, who
speaks for it?
The first question focuses then on the issues of personhood and balancing, and
the second on the issue of consent; in addition, the legal discussion will also
suggest the means which are available, to the National Commission or other organs
of government, for implementing decisions about the first two points.
Four categories of law are relevant to this discussion: constitutional,
criminal, civil, and administrative. The Constitution is in large part a document
that empowers people to do things — such as giving the President the authority to
make treaties and the Congress the power to "lay and collect taxes." But in the
context of regulating fetal research, the Constitution comes into play mostly as
a limitation on what the state may do, directly or by legislative authorization
to others. The provisions most likely to be invoked are the due process and
equal protection clauses of the fourteenth amendment, although it is possible
that other parts might be relevant.'' While it is imperative for American law-
makers, including the National Commission, to have constitutional law in mind
in drafting any legislation or regulations, it does not provide a particularly
im.portant source of the law on this subject because an examination of the con-
stitutional cases most on point, such as Roe v. Nade,^ demonstrates the need to
cut a layer deeper down into the underlying common law to which the Supreme
Court turned in applying constitutional doctrine to the facts before it.
Consequently, this memorandum attempts to search out and organize the
principles which can be derived from criminal and civil law decisions, as well
as from more recent statutes which have not yet been the subject of much judi-
cial interpretation. The common law of crimes (now typically codified) has
given some protection to fetuses, under the heading of homicide and assault;
much greater protection was given by statutory law on abortion, but this is an
area still very much in flux in the wake of the 1973 decisions of the Supreme
Court of the United States which in effect invalidated virtually all abortion
laws then on the books. The civil law has also recognized the fetal interest
in protection against negligent and intentional harm; this has found expres-
sion in rules concerning torts, property, and equity.
Administrative provisions that might be relevant to fetal experimentation
are of two groups, those relating to the subjects and those relating to the
researchers. First, each state has laws which provide for the registration of
births (including stillbirths) and deaths. These provisions may affect the ways
in which fetal subjects are handled and may provide guidance, which would be
relevant to the criminal and civil law, on the status of the fetal material
being used for research. Second are the disciplinary provisions which govern
researchers, particularly those who are licensed to practice a profession and
are thus exposed to penalties (e.g., censure or revocation of license) for con-
duct that violates the rules or norms established for the profession. Since
such matters rest in the hands of the profession itself (although in some ' .. ■"
instances with state sanction) and are typically not well articulated as pro-
spective rules, they add little to the law^ and will thus not be an important
part of the material included in this memorandum.
13-3
within the limitations imposed by a memorandum of this scope, an attempt
will be made to indicate the variation among states which typifies the law on
many of the points in issue here, as well as to trace the changes which have
come about in the law over time. This memorandum does not pretend to touch on
all the legal issues raised by fetal experimentation — indeed the growing body
of law and commentary on the general issues of human experimentation is treated
only tangentially . The current law on abortion is considered repeatedly because
abortion forms the backdrop, both legally and clinically, for fetal experimen-
tation. No "model statute" is offered, although the present state legislation,
which seems largely the product of haste and emotion, is analyzed where appro-
priate. This analysis makes it plain that while the topic is very complex,
anything put forward by the Commission should be as simple as possible because
the rules will have to be applied by ordinary people, often hurriedly and without
understanding .
The law operates by attempting to draw lines between what are often simi-
lar categories; thus, it is often accused of being arbitrary. But lawyers also
are keenly aware of the precedential effect of each step that is taken. The
Commission, too, should anticipate that the categories it draws rest on a blurred
reality and tend not to hold fast in practice. Hence, some margin of error and
some means of self-correction and adjustment must be included.
Any organizing framework has some problems, but it is hoped that the one
used here serves the Commission's purposes. Rather than build the memorandum
around legal categories (e.g., fetal interests shown by the criminal law, by the
law of property, etc.), it was decided to structure it from the viewpoint of
implementation — that is, according to types of research.
Analysis of both the major issues — the definition and balancing of fetal
interests and consent — should be facilitated by examining separately the various
types of fetal research, moving from experiments raising the fewest hard legal
issues to those which pose increasingly difficult questions.
II. DEAD FETUSES, TISSUES AND PRODUCTS OF CONCEPTION
The dead fetus and the products of conception (the placenta, umbilical
cord, amniotic fluid, and so forth) may be desirable objects of study because
of biomedical investigators' interest in: (1) learning about normal develop-
ment, (2) observing whether substances cross the placenta, and (3) identifying
any injuries to fetuses from products (drugs, cigarettes, food additives, etc.)
used by pregnant women. Studies of the latter types might be commenced while
the fetus was still in utero , by the measured administration of the substances,^
but they can also be conducted simply by studying the results of "natural experi-
ments" after the abortion of a fetus who was exposed to a substance in the
ordinary course of its development. There is also a great deal of interest in
studying fetal cell differentiation and development in tissue culture, and in
using such cultures for the study of viruses. Finally, organs from the recently
dead fetus may be used in such as yet experimental procedures as thymus trans-
plantation to infants with immune deficiency disease.
13-4
A. Uniform Anatomical Gift Act
All of this research would appear to be permissible under the Uniform
Anatomical Gift Act (UAGA) , which was promulgated by the National Conference
of Commissioners on Uniform State Laws in July 1968 and was swiftly adopted in
all fifty states and the District of Columbia, with only minor variations (none
of which are germane to this discussion) . A "decedent" under the Act is defined
to include "a stillborn infant or fetus" (§ 1(b)), and a "part" of his body
"includes organs, tissues, eyes, bones, arteries, blood, other fluids and other
portions of a human body" (§ 1(e)). The purposes for which gifts under the Act
may be used include "medical or dental education, research, advancement of medi-
cal or dental science, therapy or transplantation" (§ 3). Thus, the statute
seems to indicate that research of the type being considered in this section is
acceptable; the interests of medical science and of the immediate beneficiaries
of research and therapeutic procedures is great enough to justify the use of
dead fetuses, fetal issues and the products of conception, provided that proper
consent is obtained.^
The consent procedures established by the Act are of two types. The first,
which is not relevant here, is that before his death "any individual of sound
mind and 18 years of age or more" may make a gift to a medical institution (such
as a hospital, school or organ bank) or a physician of "all or any part of his
body," the gift to take effect upon his death (§ 2(a)). The UAGA also provides
that if a decedent has not indicated a contrary wish, another person may make
such a gift; the order of priority of persons who may give permission is set
forth in six classes:
"(1) the spouse, , ,
(2) an adult son or daughter,
(3) either parent
(4) an adult brother or sister
(5) a guardian of the person of the decedent at the time of death
(5) any other person authorized or under obligation to dispose of
the body." (§ 2(b)) .
The first two classes clearly have no relevance in the case of fetal
research. It is expectable that the donation of a dead fetus or fetal remains
would thus usually be made by one or other of the parents. The statute speci-
fies that a person may not make an anatomical gift if he or she has "actual
notice of opposition by a member of the same or a prior class" (§ 2(b)) nor
shall a donee accept a gift under these circumstances (§ 2(c)). Consequently,
either parent would apparently be able to prevent the use of a dead fetus in
an experiment by notifying the other parent and/or the investigator of his or
her opposition. The statute does not, however, impose any obligation to make
such inquiries (regarding the wishes of members of the same class) ; it presumes
that a gift is valid "in the absence of actual notice" to the contrary, and
insulates from criminal and civil liability anyone who proceeds "in good faith
in accord with the terms of this Act" (§ 7(c)).
An experimenter desiring to use a fetus in an experiment could get valid
permission from someone other than a parent only in the unusual situation that
neither parent were "available at the time of death" (§ 2(b)).^ Thus, even if
a guardian is appointed for a fetus prior to its death, he or she is not com-
petent to give or withhold consent for the use of the fetus in an experiment
after its death if the parents wish otherwise; only if a good faith effort to
get the permission of either parent failed because they were "not available"
would the guardian be authorized to act. It is also possible that the person
who performs an abortion and is "under obligation to dispose of the body"
(§ 2(b) (5)) might find him or herself left with the dead fetus by a woman who
departed so suddenly and mysteriously that she was not available to give or
withhold the necessary permission, which the abortionist would then be competent
to make. Yet if a researcher intends to ask for a "gift" of the dead fetus or
fetal remains, the UAGA would appear to require that he take the steps neces-
sary to obtain permission from the parents rather than from the abortionist
under a parental "unavailability" rationale (which would ordinarily be of dubi-
ous validity, given the requirement of "good faith" compliance with the statute) .
The Act also provides that authorization for the gift may be given "after
death or immediately before death" (§ 2(c)). Since the statute should be read
in the context of the common law requirements on consent, the authorization
should be both "informed" and "voluntary." It might therefore be questionable
whether permission for an anatomical gift arising in the abortion context would
be acceptable if it were obtained from a pregnant woman immediately before the
fetus died, that is during the abortion process when she may not be in a clear
frame of mind. It should nevertheless be possible to accommodate both the
statute and the feelings of the parents; an explanation of the need for fetuses,
fetal tissue or the products of conception could first be made to the pregnant
woman (and the father of the fetus if he accompanies her) at the time that the
abortion procedure itself is explained, and then permission for the anatomical
gift could be obtained after the abortion was completed. In many instances,
where the researcher's intention is to study the anatomy of the fetus or to
use tissue for culture purposes, consent to proceed immediately is not needed.
Only when the deterioration of tissues or organs (as in thymus transplantation)
would jeopardize the success of the experiment is the need for a very prompt
permission presented. Thus, such experiments can only go forward if and when
the persons carrying them out feel confident that they will not be imposing an
undue psychological burden on particular parents by seeking authorization from
them immediately after a stillborn fetus has been aborted or an aborted fetus
has died.
B. Other Laws
Although the UAGA is the major provision of relevance to research on dead
fetuses and fetal remains, a number of recent statutes modify in some measure
the law on this subject, and some much older statutes may be thought to be rele-
vant to this research as well.
In the past two years a large number of states have adopted new abortion
statutes and some have also enacted special provisions on fetal experimentation.
As a result, 14 states now have laws which restrict experimentation on aborted
13-6
fetuses, although the provisions in eight of these states apply only to live
or viable fetuses and the prohibition on research with "any aborted product of
human conception" in the California statute excepts "fetal remains."* The
statutes in the remaining five states impose varying degrees of restriction on
research with dead fetuses.
The least restrictive provisions are those of Massachusetts and South
Dakota, which hardly change the law. The former states that: "No experimenta-
tion may knowingly be performed upon a dead fetus unless the consent of the
mother has first been obtained, provided however that such consent shall not be
required in the case of routine pathological study. "^ This appears to be basi-
cally congruent with the UAGA, although it is unclear how "experimentation"
could "knowingly" take place during "routine pathological study," since the
research element would appear to lift such a pathological exam out of the cate-
gory of the routine. The South Dakota provision is even more permissive. It
prohibits only "experimentation with fetuses without written consent of the
woman. "^° The net effect of these two laws would seem simply to be that the
father of the fetus is deprived of the authority (granted under the UAGA) to be
the sole person consenting to the use of that fetus after death; the absence of
maternal objection is no longer taken to be sufficient, rather the written con-
sent of the mother is always required. Under the South Dakota statute the rest
of the UAGA schema seems unaffected, so that the actual communicated objection
of a father would still appear to be a bar to the use of his fetus; under the
Massachusetts statute, an investigator who proceeded on the basis of the mother's
consent despite the known objections of the father would not be exposed to crimi-
nal liability but he would not be immune from civil liability (to the father of
a fetus) if he went beyond "transferring" the fetus and actually experimented
upon it.
The remaining three statutes on fetal experimentation do have an impact
on research with dead fetuses. Illinois and Indiana allow only pathological
examination of, but not experimentation with, fetal tissues. -"^ Ohio narrows
this permissible category to authorized autopsies; aside from such procedures
"No person shall experiment upon or sell the product of human conception which
is aborted."-'^
It should be noted that all of these provisions, to the extent that they
modify the UAGA rules on experimentation with dead fetuses and the like, apply
only to the products of induced and not spontaneous abortions. Although the
language in a number of them is broader, this must be read in the context of
anti-abortion statutes which are speaking implicitly as well as explicitly of
"the intentional destruction of the life of an embryo or fetus in his or her
mother's womb of the intentional termination of the pregnancy . . . with an
intention other than to increase the probability of a live birth or to remove
a dead or dying unborn child," as the Missouri legislature put it.*^
The remaining set of laws which might affect the permissibility of experi-
mentation with dead fetuses are grave robbing statutes, many of which date to
the early nineteenth century. It is important to note that these would come
into play only when the researcher has failed to get adequate consent for the
use of the fetal remains.-'*
13-7
Although the applicability of grave robbing statutes may seem dubious,
the most notorious actions brought against physician-investigators for fetal
experimentation are being prosecuted under such a statute: on April 11, 1974,
a grand jury indicted Drs. Leonard Berman, David Charles, Agneta Philipson and
Leon Sabath for allegedly violating an 1814 Massachusetts statute when they
studied the fetuses which had been aborted at Boston City Hospital after their
mothers had taken an antibiotic/^ The prosecution claims that the physicians
did not have the authority to "remove or convey away" the "human body" of the
fetuses or "the remains thereof," acts which are made a crime subject to impris-
onment for up to three years.-'* The only relevant judicial interpretation of
this statute is found in Commonwealth v. Slack}^ where defendants had removed
the body of a deceased man from the house of one of the defendants where he had
died to that of a physician in another town, who wanted it for dissection.
Defendants were convicted of removing and conveying away a himian body without
proper authorization. The conviction was reversed on appeal for failure to
allege that the dead body was removed for the purpose of dissection. The Court
stated that a literal construction of the statute would seem to prohibit
removing or conveying away of any human body or the remains thereof for whatever
purpose, even the internment of a dead body. The Court said that the provision
was limited by the purposes of the statute which were to allow dead bodies to be
used with the permission of the Board of Health, the overseers of the poor, or
the selectman of the town for anatomical study, and to prevent the use of them
in all other cases. The Court also held that the statute applied to dead bodies
that were not dug up or removed from a cemetery.
The defendants in the present case possessed the requisite intent of
using the aborted fetuses for dissection, and the fact that the aborted fetuses
were not literally removed or conveyed anywhere but within the hospital grounds,
coupled with the fact that their disposal was only detained, does not completely
distinguish the facts in Slack, but only shortens the distance of removal and
the time of disposal.
The grave robbing statutes in most other states are similar to the
Massachusetts statute, and there is remarkably little judicial commentary on
them that is relevant to the fetal research case.-"^ More recent statutes, such
as the one enacted in Florida in 1972, except from their prohibition on "dealing
in dead bodies" medical schools and other institutions that obtain the corpses
for dissection or research."'®
The issues remaining unresolved, pending the final disposition of the
Boston case, are whether the remains of a fetus (such as the abortuses removed
by hysterotomy in the Boston City Hospital experiments) are "human bodies"
within the scope of the grave robbing statutes , and whether the medical practice
not to obtain explicit permission from women undergoing abortion for studies to
be conducted on their abortuses is a valid defense to the charge of grave
robbing. On the former issue, it seems doubtful that the legislatures had in
mind the products of early pregnancy (i.e., first and possibly second trimester
fetuses) when they drafted the grave robbing statutes, particularly in the
nineteenth century. On the other hand, the permissibility of abortion does not
mean that such fetuses do not possess "human bodies" even if they are not
"persons" in the full sense of the law, as the Court declared in Roe v. Wade.
One likely way to resolve this issue is by looking to the statutes which define
when a birth or death certificate must be filed; these are discussed in the
following subsection.
The defendants in the Boston case would clearly like to take refuge in
the medical practice of not seeking maternal consent for post-abortion exami-
nations. As a matter of fairness, this may be a good argument; it indeed seems
inequitable to penalize a few doctors for proceeding in good faith to do exactly
what all their colleagues regularly do, particularly when it is at least arguable
that an implied consent for the fetal examinations was given by the women when
they gave informed consent to the manipulation of their own bodies — since the
purpose of the experiment could clearly be accomplished only if the investigators
both gave the women the antibiotic and then examined the fetal tissues and organs
for its presence. Yet as persuasive as this reasoning might be in negating neg-
ligence in a civil action against the doctor defendants, it is rather beside the
point in a criminal action. The custom of a profession is no defense if it vio-
lates the law (e.g., were physicians routinely to engage in involuntary euthana-
sia this would not stop it from being homicide) , and a prosecutor has discretion
(subject to some small constraints on arbitrary or malicious abuse) as to whom
among a group of wrongdoers he will prosecute. Thus, unless the custom of the
profession, or the approval of an institutional committee on human studies,
amounts to "lawful authority" for the "remov[ing] or convey[ing] away" of the
fetuses, and thus complies with the statute, investigators who experiment on
dead fetuses without parental permission (according to the procedures of the
UAGA) are at risk of being convicted under grave robbing laws.
C. Life and Death: Definition and Certification
In the discussion thus far we have assumed that it is apparent what a
"dead fetus" is. Yet this is plainly not so. While it might be possible to
get agreement that a particular fetus had so completely ceased all functioning
that it was "dead," there would certainly be disagreement about the point in the
process at which such a conclusion is proper and more fundamentally about whether
the "death" being talked about is similar to the "death" we speak of in the case
of a person. This question shades over into the related question of "viability" —
if the judgment that a fetus is "nonviable" is based on the conclusion that its
organ systems cannot function together in a coordinated fashion, then should it
be considered "dead" although some parts of its functions can be kept working
artificially for some time? (Since the National Commission has sought a separate
memorandum on these questions, this subsection will be kept brief.)
In recent years the traditional understanding of death in human beings has
become somewhat confused by medical developments which permit the artificial
maintenance of respiration and circulation and by the ability of a heart removed
from a "dead" person to function again in the recipient into whom it is trans-
planted. Medicolegal interchange and discussion has helped to clarify this field
somewhat, however. There is an emerging agreement, both within the medical pro-
fession^" and among the formulators of public policy,^' that it is possible to
give a new articulation to the traditional understanding of death which can be
employed in all cases, whether or not artificial means of support obscure the
significance of the traditional life sign (heartbeat and breathing) . A modern
definition, which recognized the interrelationship of the tripartite system as
the basis for life and had death turn on the irreversible cessation of any neces-
sary part,^^ might be carried over into defining death in the fetus. Although
on its face the problem of defining death in the fetus seems rather different,
it is actually quite similar. In the fetus, the question is whether developing
organ systems (e.g., heart, lung and brain) can be sustained to a point v;here they
are capable of independent functioning, while in the child or adult, the question
is whether injured organ systems can be sustained to a point where they will
recover functioning.
In the case of the child or adult it may thus be proper to declare death
despite a beating heart and respiring lungs if these functions are being artifi-
cially supported because of irretrievable cessation of total brain functions.
Were it possible to achieve the necessary oxygen uptake through perfusion of a
fetus that lacked functioning lungs and thereby to maintain circulation, such a
fetus might be considered "dead" if it had no brain functions. Given the present
technical difficulties of such a maintenance procedure and of making the neces-
sary neurological findings, it seems likely that the definition of a "dead fetus"
for purposes of the type of research considered in this section will be a narrower
one. For the moment at least, fetuses which might be considered dead under the
broader definition drawn with reference to general human death can be considered
as subjects under the rubric of research on live, nonviable fetuses. The greater
restrictions which accompany such research are merely a reflection of the public
concern over the prospect of "exploitation" of apparently living, albeit hopeless,
fetuses. It is sensible to distinguish (for purposes of their use in research,
and for other purposes) between those beings, whether adults or fetuses, who are
dead and those who are so close to being dead that further attempts at lifesaving
are pointless. Yet it should be recognized that as more is learned about fetal
development, and as new means are created for determining "viability" and for
promoting it where possible, the time may come when some fetuses now designated,
out of ignorance or caution, as "live but nonviable" will be seen as being prop-
erly described as "dead."
At present the laws on death certification provide little guidance on this
question of "definition," but instead introduce another complication which can-
not be ignored. In a number of states the special category of "fetal death" is
recognized. This is typically defined as death prior to complete expulsion from
the mother, evidenced after separation by the absence of life signs such as
respiration, heartbeat, pulsation of the umbilical cord and movement of voluntary
muscles .^^ In some jurisdictions, a regular death certificate must be filed in
all cases of fetal death ,^'' while in others such a certificate is required only
after a stated period of gestation .^^ The more common practice, however, is for
a special "fetal death" certificate to be filed, usually only after 20 weeks
gestational age^^ but in some jurisdictions regardless of the length of the
pregnancy.^'
If a fetus is separated from its mother and shows signs of life (heartbeat,
respiration, pulsation of the umbilical cord, or spontaneous movements of volun-
tary muscles) it is considered a "live birth" in most jurisdictions, although
many apparently do not bother to define the term in their statutes .^^ A finding
of "live birth," which requires that a birth certificate be filed, is not
13-10
dependent on the length of gestation nor on how long the signs of life persist
in the fetus; if the life signs cease, a death certificate must be filed in
addition to the birth certificate.^^ Some states go further and require birth
and death certificates to be filed for "stillborn children," but it is more
usual to require only a report on those stillbirths that occur after 20 weeks
of gestation.^"
The laws on the filing of certificates fall into the "administrative"
category of law; that is, the form they take (with a great deal of interstate
variation)'^* is primarily directed at achieving the greatest convenience for
state record-keeping functions, although they may have the collateral purpose
of helping to enforce the criminal laws.^^ Thus, they may say something, but
probably not a great deal, about the state's judgment of the emerging "person-
hood" and consequent need for legal protection of the developing embryo and
fetus. As was suggested above, they may even be employed by courts which are
seeking guidance in determining whether a dead fetus is a "human body" within
the meaning of a criminal statute on grave robbing. But their significance
for our present concern is basically that they set forth some procedures with
which researchers using dead fetuses should be careful to comply.
Beyond this, three broader conclusions can be reached. First, that most
legislatures appear to have recognized that distinctions exist among (1) fetuses
emerging from (induced or spontaneous) abortions prior to the sixteenth or
twentieth week of gestation, (2) older fetuses which are expelled or extracted
and lack signs of life, and (3) other kinds of dead human bodies, including
those of fetuses which at least temporarily show signs of life following complete
separation from their mothers. Second, that in most jurisdictions birth and
death certificates are appropriate only when there has been complete expulsion
of a fetus which shows some signs of life at the time of separation, although
some states require both certificates for "stillbirths."
Finally, the general confusion of this area and the need to proceed with
caution argue strongly that a "dead fetus," for purposes of research pursuant
to the UAGA should be one which is "lifeless , "^-^ in the sense of lacking all
signs of life. The use of the term "lifeless" has the advantage of avoiding
the question of whether the fetus to be "dead" had once to be "alive" in the
sense of being a human being. It speaks instead to the absence in the fetus
of the signs of life which are basically indicators of functioning organs (pul-
sation, respiration, etc.); it is apparent that from an early point in pregnancy
the fetus has "life" in terms of such developing, rudimentary systems. On the
other hand, the term "lifeless" does not suggest, at least to the lay mind, that
there has been cessation of all intracellular life, which begins in "human" form
with the fertilization of the egg and which persists after the point at v/hich
the fetus would appear "dead" to any naked eye.
D. The Dead Fetus In Utero
The foregoing discussion has assumed that the "dead fetus" which might be
a subject of research was ex utero. This might not always be the case, however.
Consider, for example, a physician-investigator who wished to experiment with a
new method for extracting (aborting) dead fetuses. For reasons which appear
13-11
more fully in later sections, the investigator in this case would have to obtain
consent from the pregnant woman and only from her. The UAGA, under which the
father of a dead fetus might attempt to have some say over its disposition,
clearly was intended to apply only to independent dead bodies. Indeed, notwith-
standing the clear language of the UAGA it would seem dubious that a spouse
(class 1 under the Act) of a Siamese twin who died would be authorized to donate
the body to research without the consent of the other twin (only in class 4 as a
brother or sister) , if the twins were still attached to each other! This con-
clusion is reinforced (if more than common sense is needed) by the preceding
discussion on the death certification laws; they indicate that until the fetus
is separated from its mother it is not regarded as a separate being for whom a
"fetal death" or ordinary death certificate needs to be filed.
III. LIVE AND VIABLE FETUSES
A second category of research would be that done on living, viable fetuses,
either ex utero, as for example development of means of supporting premature
infants and of methods to prevent or treat disorders which affect only these
infants, or in utero, as in experimental means of preventing prematurity,
improving the means of monitoring the fetus during labor, or trying out new
methods of prenatal diagnosis (like fetoscopy) and treatment (intrauterine
transfusions). In addition, viable fetuses might be the indirect subjects of
research carried out on the treatment of various conditions in pregnant women.
The fetal subjects of such research are clearly at the opposite pole from
those discussed in the preceding section. Rather than being dead, they are pres-
ently functioning and have a reasonable chance of surviving with proper care--
that is, they are "viable." In some ways, then, one would expect research of
this type to be the most controversial, and it probably would be if such fetuses
were used simply as experimental subjects. But, as the examples of research
given above indicate, the intent of investigators is usually to treat the fetuses
as patient-subjects who stand to benefit from the experiment. Not only in the
investigator's conscience but in the law as well this difference in intent makes
a substantial difference in the permissibility of the research. There may, how-
ever, be times when this rationale is not open because a live, viable fetus has
become involved in research which will not benefit him, as for example, in a
controlled experiment where some of the subjects will be assigned to a procedure
(perhaps a placebo) which will not benefit them. Experimental techniques of
abortion may also occasionally be employed with live, viable fetuses in utero
and may even on occasion produce such a fetus alive outside the womb. Hence,
it is not possible to cover all experiments on viable fetuses with the comforting
blanket of "beneficial research."
A. Ex Utero
As was shown in Section II, the statutes on fetal experimentation and on
the registration of births do not regard viability as a necessary element in
"live birth." Rather, the separation of the fetus from the mother, usually
through complete expulsion or extraction, and the existence of some signs of
life are the customary indicia of birth, and hence of the creation of a new
13-12
hioman being with full claim on society's concern and protection through the
law.''* Nevertheless, the fact that a particular fetus is "viable" (a prediction
based on prior experience with fetuses of similar weight, size and gestational
age) may heighten society's concern, as is manifest in the attitudes of the
parents and the attending medical personnel.
1. Fetal Interests . Once birth has occurred, the law places definite
limitations on the extent to which a viable fetus can be involved in research;
these would be the same as those which apply to any neonate. The law recognizes
the neonate's interests in survival, in dignity, and in avoiding pain and
suffering. Consequently, the criminal law defines as homicide the failure of
parents or attending medical personnel to take reasonable steps to care for the
neonate or the taking of steps that endanger health or life if their conduct led
to the infant's death ,''^ and the civil law provides remedies if these persons
intentionally or negligently harm the neonate or neglect or otherwise fail prop-
erly to perform their duty to it.^*
These legal rules would obviously be relevant to proposed experiments with
viable fetuses ex utero in a number of ways. First, neither criminal nor civil
law would seem to stand in the way of the parents of such a fetus agreeing with
a researcher to undertake an experimental mode of therapy, provided that such
treatment (although new and perhaps even of unproven value) can be said on rea-
sonable grounds to offer some advantages for the infant over modes of treatment
that are presently available and that are foregone by the choice to use the
experimental means instead. Even were it to be provable that the infant's death
resulted from the experimental treatment (rather than from other causes, such as
its prematurity) and that death would not have occurred had the conventional
treatment been used — both obviously very difficult of proof — criminal liability
for murder or manslaughter would not exist. To constitute a defense, however,
the experimental modality must have been used in good faith and must be reason-
able. For the physician-investigator this would probably mean that he or she
can satisfy professional peers that the new treatment was as good as, or better
than, existing treatments, based on theoretical reasoning, animal testing, and
prior experience with the new treatment or others like it. For the parents the
standard of reasonableness would turn on their care in selecting the physician-
investigator and in weighing the relative risks and benefits of the alternatives.
Their choice would also have to fall within the range of community-accepted
values; despite the protection given by our constitution to individual beliefs
and the wide scope allowed for behavior which may be harmful to oneself, the law
limits a person's freedom to make choices which are harmful to others who are
under the person's care.^' The paucity of cases on point, however, makes a more
precise statement about parental discretion to choose one treatment over another
difficult. The most germane cases involve parents who were prosecuted for
failing to provide any treatment or for delaying treatment; these cases suggest
that parents will be liable if their choice fell far outside what the general
community regards as reasonable .^^
These observations also have relevance for a second situation. Suppose
that rather than enrolling the viable "born" fetus in research a parent or
physician-investigator were to decline to permit the neonate to be given an
experimental treatment although no other means exist to keep the child alive.
Although the distinction between "ordinary" and "extraordinary" procedures has
not been formally adopted into the law,^' these concepts are closely related
to the standard of "reasonable efforts" and so may be useful in this analysis.
All experimental modalities would seem by definition not to be "ordinary" —
rather than being customary, common or part of normal practice they are to some
degree unusual and outside normal practice. But this is clearly a matter of
degree, and some interventions that are classified as "experimental" for purposes
of funding or institutional review procedures might involve such a slight devi-
ation from the usual mode of treatment as not to be "extraordinary." Yet the
smaller the innovation the greater the likelihood that there is an acceptable
"ordinary" mode of treatment which would be offered as an alternative; hence,
the less likely that the neonate would be left without any treatment whatsoever
by the refusal to permit it to participate in the experiment. When such refusal
is based on a reasonable effort to compare the risks of the experiment with the
benefits to be derived by their neonate-sub ject, including in the calculation
the pain and discomfort involved as well as the degree of recovery expected, it
is highly dubious that the parents or physicians would be liable for homicide
or criminal neglect.
The third point about ex utero research with viable fetuses on which the
law may shed some light arises when the research proposed is not intended to
benefit the fetus directly .*° As an initial matter, it is obvious that, under
the rules just articulated, there would be no grounds for holding criminally or
civilly liable a parent or physician-investigator who declined to involve the
fetus in such an experiment even were it later to appear that the experimental
procedure would fortuitously have been beneficial or that its absence was in
some unexpected way harmful to the fetus. But what of enrolling a viable fetus
in a nonbenef icial experiment?
Since the viable fetus ex utero is in a position like that of the pre-
mature infant, it ought to be given the same protection accorded an infant.
The difficulty is in knowing just what that protection is. At one extreme, it
is well settled that an infant, or other nonconsenting person, may not be used
in nonbenef icial research which exposes it to death or serious injury. Were
death to follow, the persons responsible (parents, investigators, and so forth)
would be guilty of murder if they acted intentionally, knowing that the experi-
ment placed the life or health of the fetus at risk, or of manslaughter if they
proceed in a grossly negligent fashion without regard to the potential adverse
consequences for the fetal subject. If the fetus were injured but did not die,
the conduct would amount to assault and child abuse, and even before injury
occurs there would appear to be a violation of statutes prohibiting "neglect,"
which would seem to occur not only in the failure to provide adequate medical
care,*-' but also in the doing of anything which in effect negates medical care
and thereby imperils the infant's life or health.
The more difficult questions really arise when one begins with research
which falls at the opposite extreme. Although no one would appear to have the
authority to volunteer another, nonconsenting person for nonbenef icial research,
there are probably some studies that involve so little risk (while still pro-
viding information which may be useful to medical science and perhaps to society)
that it is hard to know on what grounds they should be prohibited. By definition,
such research would not interfere with the viable fetus' interests in survival
or in being free of pain. What, then, of its interest in human dignity, in not
being used as a thing for the objectives of others? This is a genuine interest,
and one which is certainly recognized by the law/^ In the case of risk-free
research of scientific worth it is hard, however, to see that this interest is
being denied; indeed, it may even be promoted. If a person, at no risk to him-
self, can aid others, is that not the proper thing to do? Would one not com-
plain of an assault on one's dignity if he were prevented from doing such an
act? Obviously, in the case of a neonate this argument should not be pressed
too hard — the neonate is unaware of when a choice is made that it should pass
up a chance to help others, so its sense of dignity is not likely to be much
harmed. But, while there is danger that the rationale of "helping others"
could become an excuse for using viable fetuses improperly in nonbenef icial but
risky research, in the case of nonrisky research the rationale really gives
voice to the common sense perception that such research is not offensive. More-
over, there is the utilitarian argioment that society will be better off for such
research, which in turn suggests that it may even be beneficial for the fetal
subject, for it is only through the collective enterprise of research that the
members of society, including the viable fetus ex utero, mutually bestow the
benefits of new biomedical knowledge on one another.
As one moves away from this polar case — involving research along the lines
of taking measurements of the neonate — and adds increments of risk or of pain it
is hard to know where the line should be drawn. Professors Henry Beecher and
William Curran have argued that minors may be used in experiments of no direct —
and in some instances, no indirect — benefit to the child, *^ without specifying
a limit to the amount of danger which such experiments should be allowed to
pose. Most commentators read the case law as providing no warrant for such a
sweeping conclusion,*" and the unsettled nature of the law is indicated by a
lawsuit brought by a member of the Human Studies Committee at the University of
California Medical School to obtain a declaratory judgment on the legal rights
and authority involved."^
As a practical matter it should be borne in mind that unless the law is
clarified through a declaratory judgment or through the promulgation of authori-
tative regulations, it is most likely to evolve in cases brought against parents
and/or physician-investigators after injury to a viable fetus has occurred. The
defendants in such a setting are at the disadvantage of having to insist that
the experiment was not risky or involved only very minimum risk in the face of
the fact that the subject actually was injured in the course of the procedure.
This does not mean that they are sure to lose in such cases, since the burden of
proof rests with the plaintiff-fetus or the public prosecutor as the case may
be. But it does suggest that great caution be used in the design, approval or
execution of experiments on the viable fetus. The overriding responsibility on
all parties is to promote the health and well-being of the fetus by all reason-
able steps and to take no actions which jeopardize that health or life unless
they are necessary to secure some benefit to the fetus.
Although the recently enacted statutes in 14 states'*^ which contain restric-
tions on experimentation with live fetuses from induced (but not spontaneous)
13-15
abortions might seem to alter the definition of the interests involved or the way
in which they are usually balanced, only six of the statutes even appear to change
the law. In seven of the other states, the statute, like the common law, explic-
itly permits research which is intended to preserve the life or health of the
fetus ,^^ and in the remaining state (South Dakota) the statute merely prohibits
experimentation with a fetus to which the mother has not given "written consent."
The six states which have adopted "tough" anti-fetal experimentation laws
probably did not intend to prevent physicians from employing experimental tech-
niques in an attempt to save the lives of aborted fetuses. Were the language
of these statutes taken literally, the legislators would seem to have decreased
the weight accorded to the interests of a viable abortus which parents and phy-
sician want to save by using novel and extraordinary means; at the very least
they seem to have reached the judgment that all experimental interventions are
more dangerous than helpful for such abortuses. Yet this reading of the stat-
tutes is at odds with their other provisions** and with a more careful search
for their intent."^ Thus, it seems fair to conclude that none of these statutes
should be taken as having brought about a change in the common law.
2. When Do the Interests Attach? As will be discussed below, the fetus
in utero is not without protection from the criminal and civil law. But the
protection described in the preceding subsection revolved around the fetus being
a "person" in the eyes of the law. When do the interests associated with this
status attach? The general rule, already stated, is that they are owed once
"live birth" has taken place, which is in turn defined as the separation of the
fetus from the mother with heartbeat, respiration, or other signs of life. A
somewhat clouded question is presented, however, whether "separation" occurs
only upon "the complete expulsion or extraction from its mother of a product of
human conception, "^° as is generally stated in the statutes on birth certifi-
cation, or whether it can occur at an earlier point in the process of birth.
This issue could be of real importance to a researcher engaged in the study of
methods of abortion or other procedures which presented the undesired possibility
of the live-born fetus. The generally accepted common law view,^^ which accords
with the statutes, provided the basis in the recent trial of Dr. Kenneth Edelin
in Boston for the instruction given by Superior Court Judge James P. McGuire to
the jury that "for the defendant to be found guilty in this case, you must be
satisfied beyond a reasonable doubt that the defendant caused the death of a
person who had been alive outside the body of his or her mother. "^^ There was
conflicting evidence on whether the aborted fetus in that case breathed or
showed other signs of life after it was removed from the uterus; the jury's
guilty verdict may have been based on its conclusion that the fetus was alive
outside its mother's body. The jury may have concluded, however, as the prose-
cution urged, that even before this point the fetus was a person, based on the
stage of its development and upon testimony by another doctor that while the
fetus was still in the womb Dr. Edelin held onto its umbilical cord after sepa-
rating the placenta from the uterus.
It is difficult to derive much from a jury verdict under such circum-
stances, and even the appeal may not clarify the matter, since the trial judge's
instructions seem to have been in accord with the accepted legal view. At least
one state has in effect moved back the point at which fetal "personhood" com-
mences; Louisiana has created "the crime of killing a child during delivery"
which is punishable by life imprisonment in the penitentiary at hard labor.^^
The question is further confused by the oft-cited dictum of an intermediate
appellate court in California in People v. Chavez^'' that a viable child killed
during, but prior to the completion of, the birth process is a person under the
law of homicide. The Court concluded, in light of modern medical understanding
and the availability of means of caring for premature infants, that a "viable"
fetus should be regarded as a human being even though not yet removed from its
mother. It was, however, able to affirm Miss Chavez's conviction on the simpler
ground that the medical evidence was sufficient, beyond a reasonable doubt, to
support jury findings that her child was "actually born" after it was "completely
removed from its mother" and that it died because she failed in her duty to use
reasonable care in protecting its life.^^
Similarly, the Wyoming Supreme Court rejected the theory that a woman
could be convicted of manslaughter for failing to take the necessary steps in
advance to have care available for her newborn infant who died as a result;
although a parent's failure to fulfill his or her duty of care is grounds for
liability, the Court reversed her conviction because the duty does not commence
until the child is born alive.^®
Both the criminal and civil law recognize a greater burden on a physician
who is actually attending a woman in labor as compared with the duty of the
woman herself. If a fetus died after birth because of the physician's failure
to be adequately prepared, the physician could be convicted of criminal homicide
and held liable civilly for the wrongul death of the fetus. Although a phy-
sician has not contracted with the parents to care for the fetus following an
abortion, he is under a duty to it having brought about the peril in which it
finds itself.^'
In sum, in the absence of a special statute the protection of the viable
fetus which has been described here is that which is given once the fetus is in
fact ex utero.
3. Consent: No differences appear to exist so far as the interests of
the fetus based on the manner in which the viable fetus came to be alive ex
utero, but this might provide a reason for differentiating ih the way in which
consent is sought for its involvement in research. For the fetus that emerges
from the uterus as a premature neonate because of a spontaneous abortion there
would appear to be no a priori reasons for interfering with the parental control
over medical decisions which is established by the law. Thus, decisions about
whether participation in research is consistent with the fetus' interests would
be left with its mother and father (if the latter is available) within the
limits set out above.
During the congressional debates on the bill to establish the National
Commission, it was suggested that a woman who permits her fetus to be aborted
has thereby disqualified herself from having any further say over it, should
it emerge from the abortion process alive. There are other examples in the
law of a person rendering him or herself unable to exercise powers otherwise
possessed because of his or her attitude or conduct. For example, a judge who
has an interest in the outcome of a case, who is biased for or prejudiced
against a party, who has previously represented a party or was associated in
the recent past with the attorneys for one of the parties, who is a material
witness in the case in litigation, and so forth, should either recuse him or
herself or may be disqualified upon motion of one of the parties. Yet the
analogy to judicial disqualification is not very persuasive for two reasons.
First, there is a long and well articulated history of such disqualification,
with statutory and common law which spells out the circumstances that require
or permit a judge not to hear a case. This is in contrast to the vaguely based
presumption behind the disqualification of parents in the abortion context.
More important, the underlying principle for judicial decision making is that a
judge should be completely objective and disinterested. In contrast, a parent
is not disqualified from making choices for his or her minor children because
he or she is not wholly impartial. Indeed, parents' concern for their children
makes them highly subjective decision makers, and the need to balance the com-
peting claims of family members renders it unlikely that parents have the sort
of independent detachment desired for decision making on the bench. Thus, while
the general illustration of conflicts of interest may be of some value, judicial
disqualification does not supply solid ground from which to launch rules about
fetal experimentation.
A closer parallel may be provided by the rules on the removal of guardians.
The major reason for removal of a guardian is the finding of a conflict between
the pecuniary or property interests of the guardian and the ward. In the case
of a "natural guardian," such as a parent, conduct which is clearly illegal or
immoral would warrant removal. 5* A parent may also forfeit or waive his or her
right of guardianship by knowingly and willfully abandoning the child, or, having
the ability to do so, failing to maintain it.^'
The question thus arises whether the decision to abort ought, by analogy,
to disqualify the parents (or at least the mother)^° from exercising further
control over the fetus once it is alive ex utero on the ground that they have
behaved immorally and illegally regarding its interests or have abandoned it.
An affirmative answer to this question has much to recommend it since it is
plain that the parents have certainly exposed the fetus to greater burdens
than it would have experienced had its gestation in utero not been disturbed.
Nevertheless, it is hard if not impossible to conclude that the decision to
abort provides simpliciter the basis for disqualifying the parents as the
natural guardians.
The argument for disqualification faces at least three problems. First,
since the Supreme Court has declared that women have a constitutional right to
abortion, basing maternal disqualification on the exercise of that right smacks
of an unconstitutional penalty or burden. It would appear likely that automatic
revocation of parental decision-making authority could chill the exercise of the
abortion option because it would face women with the prospect of an infant to
whom they are psychologically attached and whom they have an obligation (morally
if not legally) to support without the concommitant power of decision which
usually accompanies such obligations.
Second, it must be assumed that the abortion itself was legal and hence
did not deprive the fetus of any rights which the parents were obliged to pro-
tect; moreover, there is no basis for assuming that it was immoral as to the
fetus because it may have represented the result of a very conscientious
weighing of the relative advantages to the fetus of being born or being aborted.
13-18
Third, the rule of disqualification seems to be based on a misperception
of the significance of the parental choice. Even when a woman has opted for
an abortion on the grounds of her own interests and not because she believes
this to be best for her fetus, she has not necessarily cast herself as being
irrevocably opposed to the fetus' interests. The decision to abort what is
believed to be a nonviable fetus has two parts: (1) that the woman will relieve
herself of the burden of pregnancy, and (2) that there will be no live issue
from the pregnancy. If, however, a live, viable fetus does result, then only
the first of the maternal desires has been accomplished because the second one
was based on an erroneous assumption. At this point, there is nothing in the
law which says the woman should be regarded any differently than a woman who
decided, for legally sufficient reasons, to abort a live viable fetus, i.e., to
deliver prematurely. Such a woman is bound by the duties already spelled out
which are intended to safeguard fetal well-being, and she would be assumed quali-
fied to exercise choice about how best to carry out her duties unless and until
her conduct demonstrated that she was not able or willing to do so*' and was
consequently exposing the infant to unreasonable risks.
As subject as they are to misuse, neglect proceedings at least provide a
forum for the balancing of parental rights against those of the child and the
state according to some principles and with an eye to the facts of the case.®^
This seems preferable to an absolute presumption for all cases. Moreover, it
may provide greater protection for fetal interests. Parents who are operating
within the scope permitted by the law are probably better situated than a judge
or other state official to do what is best for the particular neonate, so far
as medical care and participation in an experiment are concerned.
Nevertheless, a number of states have written some form of parental for-
feiture of rights into their abortion statutes. Louisiana, which goes the
furthest, places a live fetus vjhich survives an abortion within its definition
of a neglected or dependent child, and gives jurisdiction over it to the juve-
nile court .^^
Missouri also considers such product of an abortion "an abandoned ward of
the state under the jurisdiction of the juvenile court" over which the mother,
and the father if he consented to the abortion, "have no parental rights or
obligations."*^ These strictures apply, however, only if the abortion was not
performed to save the life or health of the mother — a limitation of some prac-
tical as well as theoretical significance. As a practical matter, a live fetus
is likely to survive only abortions performed in the third trimester; at' this
point the fetus is likely to be (or nearly be) "viable," which means under
Missouri law that such an abortion could only be performed if necessary to pre-
serve the life or health of the mother. Hence, the forfeiture of parental
rights is made inapplicable to the situation in which it most likely would
apply .*^ Furthermore, the Missouri statute serves to undercut the whole analogy
to the disqualification or removal of "biased" decision makers, because it indi-
cates that where the mother's interest is the greatest (i.e., to preserve her
life or health) she does not lose her authority over the fetus by acting
adversely to its interests.
13-19
The Montana statute also excepts abortions performed to preserve the woman's
life, but goes further by providing that the parents can retain their authority
if they agree prior to the abortion, or within 72 hours thereafter, to accept
parental responsibility for the living fetus ex utero.** Similarly, Kentucky
allows the parents to object within 10 days to the child becoming "an abandoned
ward of the state. "^' Indiana puts the shoe on the other foot; an aborted fetus
becomes a ward of the state if its mother (and father, if they are married) signs
a custody release and does not retract it prior to the abortion.*^ Finally, the
South Dakota statute provides that facts about the abortion are relevant evidence
in any proceedings to terminate parental rights or to adjudicate a live-born
fetus a dependent or neglected child;®' the usual procedural rules and burden
of proof are not short-circuited, and neglect proceedings would probably only be
brought, and would largely be decided, on the basis of conduct after the abortion
which showed that the parents — by submitting the fetus to dangerous experiments
or otherwise failing to provide it ordinary care — were not the proper guardians
of its interests. All these statutes, except perhaps those of South Dakota and
Indiana, appear to be constitutionally suspect .^° It seems better, as a matter
of policy as well as constitutional law, to presume that parents retain control
over their live, viable fetuses ex utero, and that the experimenter and the state
would look first to the parents to protect the rights of any fetal subject of
research .
B. In Utero
Although "viability" was seen not to be an important factor in considering
the interests of the fetus ex utero it has played some role in differentiating
fetal rights in utero. This is perhaps ironic since an accurate judgment about
the viability of a fetus once it has emerged from the uterus is usually much
easier to make than about the fetus while it is still en ventre sa mere. Never-
theless, the concept of viability has been employed by both the criminal and
civil law.
1. Fetal Interests. As must be abundantly clear by now, the viable fetus
has traditionally been said to achieve the interests of a full person only upon
live birth. Thus, in utero even its interest in life is not protected by a
homicide statute .^^ A recognition of this principle underlies the Supreme
Court's abortion opinions, since they permit a pregnant woman to take steps, in
order to preserve her own health, which could extinguish the life of her viable
fetus. This does not mean, however, that the viable fetus in utero is without
protection of the law; there are two ways relevant to drawing up rules on fetal
research that its interests are recognized by the criminal law, upon which the
civil law has further expanded.
First, in the wake of the abortion decisions some states have sought to
safeguard the fetus in utero against intentional injury which threatens its life.
Such statutes, like the Louisiana law on "killing a child during delivery" set
forth above ,^^ must be drawn narrowly so as not to favor the interests of the
fetus over those of the mother, since the Supreme Court has determined that the
state's interest in protecting the potential but not yet fully matured life of
the fetus must give way to the mother's interests in life and physical and mental
health.''^ An older type of statute — prohibiting "feticide" — departed from the
common law rule by making it murder or manslaughter to kill an unborn child
that is "quick. "^'' Although these statutes have not yet been reevaluated by
the courts in the light of Roe, it is unlikely that they would come into play
in fetal experimentation. Conviction of feticide, the courts have held, requires
proof that the injury inflicted upon the mother of the unborn child which caused
her to miscarry was done with malice^^ and with an intent to kill or do great
bodily harm to the mother.''® Thus, an investigator studying, for example, a new
means of fetoscopy who accidentally killed a fetus and provoked a miscarriage
would not be guilty of feticide, since he would lack the requisite intent.'^
The second way in which the law recognizes some interests of the fetus is
by protecting it against injuries which occur before its separation from its
mother and which then cause its death or impairment after it is born alive. The
most dire consequences for the parents or physician would come under the criminal
law, which regards it as murder or manslaughter if prenatal injuries bring about
postnatal death .'^ Thus, a researcher who gave a drug to a woman which caused a
lethal deformity to occur in her fetus could be convicted if the fetus is born
and then dies from the deformity; the mother could be regarded as an accessory
or conspirator if she acted with the requisite knowledge. The effect of the law
is therefore to put pressure on people to make sure that a complete and "effec-
tive" abortion is undertaken.
Suppose that, instead of investigating the effects of a drug, the research
project was trying to develop a better means for late-term abortions, and that
in the course of it a fetus was injured, emerged alive from the abortion, but
then died of the injuries inflicted by the investigator. Under the law, this
would seem to amount to homicide, but a number of defenses might be raised.
First, the physician might argue that he injured the fetus at a time when its
death was imminent (from the abortion) and thus his action should not be viewed
as significant. This defense (which is complicated because the researcher was
responsible for both the particular injuring act and the abortion as a whole)
will avail him naught; it is well settled that a person is guilty of homicide
for merely accelerating the demise of a dying person .^^ Second, the physician
may defend on the basis that the method he was using was necessary to preserve
the mother's life or health; if true, this should probably be a good defense,
because under Roe v. Wade the woman has a right to abort even a viable fetus to
protect herself against the "distressful life and future" and the psychological,
social and medical harm that "additional offspring" may impose. ^° Thus, the
viable fetus' interests, which may be seen as being strong enough to resist the
claims of science presented by the first hypothetical experiment, may have to
yield to the mother's claims in this hypothetical abortion experiment.
What understanding can be derived from these two examples of fetal research?
They may suggest that no nonbenef icial research should be permitted on viable
fetuses (or even earlier, on "quick" ones) because the law recognizes that an
injury done to such a fetus will make the investigator (and probably the mother)
culpable of homicide if the fetus is born and then dies of the injury. Yet the
fact that culpability does not attach if the fetus dies — naturally or otherwise —
in utero seems to suggest that the law's real concern is that no one be born with
a serious injury; this is a recognition, in other words, not of fetal interests
but of the interests of human beings, after birth, not to suffer and be at risk
13-21
of dying because of the culpable acts of another person.®^ Although this latter
reading of the criminal law almost seems compelled given the lav; on abortion,
easy resolution of the issue is made impossible once one takes the civil law
into account.
The civil law, which was for a time congruent with the criminal, has now
developed some theories which would seem to recognize a broader fetal interest
in protection against harm in utero. As Justice Blackmun wrote:
"[T]he traditional rule of tort law had denied recovery for prenatal
injuries even though the child was born alive. That rule has been
changed in almost every jurisdiction. In most States recovery is
said to be permitted only if the fetus was viable, or at least quick,
when the injuries were sustained, though few courts have squarely so
held. "82
Having overcome its fear that it is too difficult to prove that injuries in utero
are the cause of defects or even of death, and having rejected the concept that
the mother and fetus are a single entity so that there can be no separate injury
to the fetus ,8^ the majority of courts are satisfied to draw the line at viability
"If the mother can die and the fetus live, or the fetus die and the
mother live, how can it be said that there is only one life? If
tortious conduct can injure one and not the other, how can it be
said that there is not a duty owing to each?"^^
Not all courts have been willing to follow this reasoning to its logical
conclusion, however. About half (thirteen) of the jurisdictions which have con-
sidered the issue hold that although the fetus may be a separate entity capable
of being acted upon at viability, there has been no harm to a person until the
fetus is born alive and undergoes the suffering and medical expenses which were
caused by the defendant's act.^^ In the language of the New York Court, the
wrongful conduct creates only "conditional prospective liability" prior to the
fetus' live birth.** But an increasing number of courts (21 at last count) are
willing to recognize a cause of action for injuries to a viable fetus which
leads to its stillbirth .^^
It is these rulings which appear to depart from the law established in the
criminal context, as glossed by Roe v. Wade. Justice Blackmun attempts in that
case to distinguish recovery for the wrongful death of still-born fetuses on the
ground that this really vindicates the right of the parents to recover for their
loss. Yet some jurisdictions allow the estate of the fetus, as well as the stat-
utory beneficiaries, to recover for the actual pain and suffering prior to death.
Before concluding that such rulings would (or should) be reversed under the
Supreme Court's articulated rule that the unborn are not "persons" under the
fourteenth amendment, one must remember that "unborn children have been recog-
nized as acquiring rights or interests by way of inheritance or other devolution
of property and have been represented by guardians ad litem. "^^ Once the fetus
is viable, so that the state's interest in it becomes "compelling" since the
fetus "has the capability of meaningful life outside the mother's womb,"*^ Roe
does not appear to be an absolute bar to holding that the fetus (as well as its
parents) has an interest in its own "potentiality for life" and that actions
which interfere with that interest injure the fetus in a present sense. Thus,
the fetus may be represented by a guardian who would attempt to enjoin the inju-
ries before they occur, and its estate may collect if the injuries nevertheless
occur and cause the fetus' death in utero.
2. Consent. This resolution of the question of the interests of the
viable fetus in utero brings us squarely to the issue of "consent," or "who
speaks for the fetus?" Actually, this issue may be less perplexing than it might
at first appear. From the viewpoint of the criminal law, the fetus is not a per-
son until it is born, yet the state is still free to protect its interest in this
potential person by penalizing conduct which endangers its life except the exer-
cise by a woman of her right of privacy which "is broad enough to encompass [her]
decision whether or not to terminate her pregnancy . "^° In the exercise of that
right, she is given the power of consent — both for herself, since the interven-
tion is one into her own body, and on behalf of the fetus as parent and custo-
dian. Actions taken by others pursuant to her consent are permissible, but
otherwise may be culpable. Similarly, the civil law recognizes the parental
interest in the developing fetal life and it may also recognize the fetus' own
interest in health and life. These interests must bow to those of the mother if
in making a medical decision for herself (including participation in experimental
treatment for her own needs) she must trespass upon them, but otherwise they are
paramount. Thus, there would appear to be no warrant for parents or others to
expose the viable fetus to any other kind of experiment which poses genuine risk
to its well-being, unless those risks were the necessary price for some counter-
vailing benefit to the fetus. This resolution of the question of consent thus
places the viable fetus in utero in approximately the same position as a fetus
that has been born, though it should be recognized that both as to criminal and
civil protection at the moment, not all jurisdictions accord such a broad scope
to the fetus unless and until its injuries are manifest after it is born alive. '^
IV. LIVE BUT NONVIABLE FETUSES
Research on fetuses that are nonviable but possess some vital functions is
the most troublesome area of fetal experimentation. On the one hand, apparently
important studies have been proposed which are intended to yield information not
otherwise available about normal fetal metabolism and drug safety during preg-
nancy among other things. On the other hand, the treatment of a nonviable fetus
differently than one would treat a viable one is problematic since the judgment
on viability is only a statistical one and may be altered by changes in the
diagnosis or in the condition of the fetus. Furthermore, the vulnerability of
the fetus and the perception, at least by some people, that it is "human" in
significant ways, makes the prospect of such research a highly charged emotional
issue and a matter of legitimate social concern. Much of the law which relates
to this subject has already been discussed in the previous sections in examining
what the law has to say about research in the viable and the dead fetus, but new
strands will enter the analysis which follows.
A. The Meanings of "Nonviable"
An initial question is what is meant by "nonviable"? In the context
used here, it may appear to be equivalent to "previable." But the previable
fetus in utero obviously has the potential to become viable if left to continue
its gestation; for it, previability is merely a stage toward eventual life. The
same is not, of course, the case with the previable fetus ex utero. If the con-
cept of viability is to have any meaning, it must be that when it does not exist
the fetus is incapable — in its present locale (be it a uterus or a hospital unit)
and with the present level of medical technology — of surviving more than a short
period. Thus, for the fetus ex utero there may be no distinction between being
previable and being nonviable for other reasons; that is, both categories suggest
that a presently "living" fetus (i.e., one possessing some vital functions) is
actually "dying" either from prematurity or from other conditions inconsistent
with normal development and survival.
In the context of research ex utero, then, should there be any distinction
drawn between a previable fetus and one which is dying? If the sole concern of
the law were with preventing any significant injury that could diminish the like-
lihood of survival, the answer should be "no." Neither type of fetus has any
real prospect of continued life. The significance of this response is that
research with the nonviable fetus would then be treated the same as research with
the viable fetus, and any nonbenef icial research which accelerated the complete
cessation of vital functions ("death") would be forbidden .^^
But there are other interests beside survival that the law is concerned
to protect, prime among them the avoidance of pain. In the case of the fetus
ex utero a focus on pain might prompt a distinction between the previable fetus
and other nonviable fetuses, premised on the differences in their physical and
mental development. Up until the point at which the fetus is able to feel pain
in the sense that term is used with other persons, the concern of the law with
protecting it may be less; after that point (which may perhaps be before viabil-
ity) the fetus' increasing perception of pain would suggest that it be treated
lilce a "dying" subject. Thus, for the purpose of deciding about fetal research,
viability may be less important than other factors.
The law's further concern, which is to promote dignity and autonomy, has
less relevance to the fetus. The concepts are premised upon the present or
future capacity of the subject to perceive him or herself as a person. In the
previable fetus it seems doubtful that such capacity exists or will ever exist.
Indeed, it may even be questioned whether the interest in avoiding pain and suf-
fering does not itself require that the fetus eventually become a self-perceptive
person. Are we concerned to avoid pain in the sense of the absence from the
world of certain electrical impulses in nerve cells? Or is that preference based
on keeping people from being aware that they are suffering or that they have
suffered in the past? If it is the latter, pain experienced by a fetus that will
never be viable may not derogate from our objective since the fetus will never
have such a perception. Perhaps, instead, the societal choice is based on some
intermediate view about why injuries should be guarded against or upon other
interests .'■^
In sum, while the term "nonviable" can be used to include a fetus that is
far enough along in gestation to survive but will be unable to do so because of
particular defects, there are good reasons for limiting the meaning of the term
to those fetuses which are not sufficiently developed ever to become capable of
maintaining heartbeat and respiration on their own. It may turn out, however,
that for purposes of society exercising its protection over the fetus, viability
is less relevant than the point at which the fetus develops a nervous system
which can perceive "pain."
1. Balancing the Interests. As we have seen, nonviable fetuses ex utero
have been regarded as persons under the common law of crimes, protected against
murder and assault;^* under statutory law a still greater burden of care (than
might be warranted by its "nonviability" ) may be imposed, as in some abortion
laws,^^ and restrictions may be placed on what can be done with it, as in the
statutes governing what Louisiana vividly denominates "the crime of human experi-
mentation."^^ The common law of torts and property, and the rules of equity,
also regard the nonviable fetus ex utero as a "person" to be accorded the full
protection of the law. Although its small size and weight and general lack of
development preclude such a fetus from having any true independent existence,
the fact of its physical separation from its mother is sufficient to confer upon
it the presumption of such independence.
Whether this is a wise result is another matter. The law's protection is
conferred upon the fetus in part because of society's skepticism about the accu-
racy of determinations that a particular "nonviable" fetus has no prospect what-
soever of surviving; when a life is at stake, great scrupulosity is demanded.
Against this must be weighed the possibilities foregone. It is a matter for
policy determination, not derivable from the law, whether a particular incursion
on the interest of the fetus is justified. If one is speaking of very young
fetuses (say, 12 to 18 weeks), in which the diagnosis of nonviability (by size,
weight, etc.) can be made with great certainty, thereby eliminating the possibil-
ity of survival to a point where the concerns of suffering and autonomy would
come into play, it is for society to say whether there are persuasive reasons
for exposing the fetus to some risk for the benefit of society, as through par-
ticipation in an experiment. If the fetus is sufficiently immature that concern
over any present awareness of pain can be eliminated, the horizon of permissible
experiments might be expanded accordingly. . .
Would a law which permitted experimentation, under specified limits and
controls, with nonviable fetuses ex utero run afoul of any legal standards? The
claim might be made, on behalf of such fetuses, that they would be denied the
equal protection of the laws if they could be subjected to experiments without
their consent but other persons could not be and if investigators would escape
criminal and civil liability for injuries done them but not other persons. It
might also be said that any legislative redefinition of personhood which excluded
them would amount to an arbitrary deprivation of due process, just as if all
13-25
children under twelve or all women were declared not to be "persons." But both
of these arguments beg the real question, which is whether actual differences
between nonviable fetuses and other beings are great enough to justify a distinc-
tion drawn for the purpose of permitting a certain class of research. That is
the sort of judgment on which the National Commission has been asked to give an
opinion. Ultimately, legal rules drawn for other purposes do not appear to offer
very good pegs on which to hang one's hat. The choice of "birth" (i.e., emer-
gence from the mother with some signs of life) as the pivot point for "person-
hood," regardless of viability, was made in the context of different competing
interests (such as a person's hypothetical interest in being free to kill a new-
born baby, or to behave negligently toward it) than those interests (such as the
advancement of biomedical knowledge and the provision of new therapy) which pre-
sent themselves in the present context. Obviously, the balancing of different
sets of interest may lead to different conclusions; moreover, the interests them-
selves may be subject to redefinition. The point of birth (independent of via-
bility) provided a standard which was easily administered in all sorts of set-
tings— from spontaneous abortion at 24 weeks in a taxicab to premature delivery
in a hospital. It is open to question whether some other line, dependent upon
a more precise and thorough determination of viability, might not lead to a dif-
ferent description of the rights of the beings falling on either side of the line.
2. Consent. If it is concluded that the nonviable fetus ex utero is to
be regarded like any other incompetent person, and thus available only for bene-
ficial research or for research which poses absolutely no risks, then consent
should be fairly straightforward. The same rules would apply as governed the
giving of consent for the viable fetus ex utero ?^ There is no need to repeat
here the reasoning which concluded that the decision-making power should remain
with the parents, subject to revocation if their decisions viz-a-viz care or
participation in an experiment show them to be at odds with the established
rules of civil and criminal law which are designed to protect all persons against
harm.
Were a wider range of experimentation to be allowed, more difficult issues
of consent are presented. The law's recognition of the parents' rights as "natu-
ral guardians" to give or withhold consent for the use by others of their dead
as well as living offspring®^ would seem to argue that they should at least have
the authority to refuse to permit their nonviable fetus to be used in an experi-
ment. There appears at this time at least to be no convincing argument made
that the state needs, in order to secure collective benefits, to intervene and
conscript fetal subjects. ^^
In any case, it must be asked whether the parents' consent is sufficient
to permit participation in experiments which are no longer limited to those that
involve no risk or may be beneficial. The fact that such an experiment would
have to be justified on the basis of its collective benefit (via scientific
knowledge) might suggest that the decision on participation should be made by a
representative of society, but it might equally argue that such a person should
be kept at arms length since he represents an interested party. The decision
might, therefore, be left in the hands of the parents, with some review by a
disinterested person, like a judge, concerning either (1) broadly, whether all
the relevant factors have been taken into account in the parental decision making
and whether there is any affirmative evidence that the parents are acting
irresponsibly or maliciously in their choice, or (2) more narrowly, whether cer-
tain specified, minimal criteria, about the certainty of the diagnosis of "non-
viability" and the degree of risk involved, have been met. In the organ trans-
plant field, the advance approval of the courts has on occasion been sought for
the removal of an organ or tissue from a minor; the parents' approval was not
regarded as sufficient because there was thought to be no benefit to the donor,
and because the parents were perceived to have a conflict of loyalties between
protecting their well and healing their sick children. The entire cast of these
cases suggests that they were intended more to benefit the adults involved (by
protecting them against liability for battery once the donor came of age) than
to protect the donors from harm. The early cases on kidney transplants between
identical twins ■'°° were decided on the dubious basis that the donor obtained a
psychological benefit, and this rationale has been repeated in cases to which
it has increasingly attenuated application; now courts have, without explanation,
approved the transplants (of bone marrow) in cases where the donor was too young
to receive any psychological benef it.''"-' While the experience with judicial
review of parental choice in this area is thus not encouraging, this does not
mean that a judge or other special decisionmaker could not play a useful role
in reviewing parental decisions about fetal experimentation.-"'^ "Broad" review
(as described above) would be most likely to protect the fetus against the ill-
motivated or ill-informed parent, but would involve a large administrative
expense and perhaps impossible delay. "Narrow" review might be nothing more
than an extension of the approval necessary to be obtained from the institutional
review committee prior to any research; it would not be concerned with the basis
of parental choice, but merely with assuring that each fetus came within the
diagnostic criteria of eligibility for the project.
C. In Utero . . . - t ' . .
Not surprisingly, the law has generally regarded the nonviable fetus in
utero as having the least well developed set of interests. Not yet visible to
the naked eye as a being separate from its mother (like a fetus ex utero) nor
even capable biologically of having a separate existence (like a viable fetus),
a fetus of this class still enjoys many forms of legal protection though far
fewer than the others we have discussed.
1. Balancing the Interests. Live birth following an injury is the sine
qua nan of liability, either for homicide or assault. For crimes not requiring
live birth, quickening is the touchstone, since it provides the necessary assur-
ance that there is a life which might be endangered. The common law of abortion
is a tangled web, but the best historical view is that bringing about an abortion
was no crime at all before quickening ;'°-^ the feticide statutes are to a similar
effect.^°* But as abortion statutes were first adopted and then revised the
quickening distinction disappeared. There is good reason to believe that this
reflected a social desire to protect women from the dangers of abortion, ^"^ rather
than a belief that the fetus was an entity deserving full legal protection from
the moment of conception. At any event, the Supreme Court plainly adopted a
view of history and of the interests derived therefrom which accepts that an
unborn fetus does not receive full recognition and protection prior to birth and
certainly not prior to viability .i°®
13-27
The civil law has not spoken with one voice on the question of the pre-
viable fetus' rights. The law of property for a long time gave the greatest
recognition, since a child from the point of conception was able to acquire
property interests and was treated as being "'born' and 'alive' for all purposes
for his benefit. "■'°' Professor David Louisell has suggested that the presence of
live-born children before the courts in all the cases was merely a happenstance
of litigation timing, and that judicial observations that the child must be born
alive for its property interests to vest are "really gratuitous and superfluous"
and "only dictum. "^°^ Cases have said otherwise'"'' and the language of many stat-
utes'^" is explicitly contrary to this view.m Thus, the cases may signify
nothing more than a recognition that it would be unfair to exclude a posthumous
child from its share of an estate rather than demonstrating any strongly held
common law belief that the previable fetus is a person.
As already shown, the law of torts has recently moved from a niggardly
view of the fetus' interests to a very expansive one.'^^ For the child born
alive, it seems to be of no importance to most courts which have addressed the
question whether the injury which causes impairment or death occurred before or
after viability .^''^ Again, the significance of these cases is unclear. Certainly,
a research project should not expose even a nonviable fetus to injury if it is
later to be born — the law attempts to protect people against injury, even when
the harmful conduct occurred before the time of personhood. Allowing recovery
for injuries occurring prior to viability simply recognizes the reality of bio-
logical cause-and-ef feet : although not yet an independent being, the early-term
fetus is capable of being injured, and indeed is highly susceptible to certain
kinds of injuries.''^
No jurisdiction seems, however, actually to have allowed recovery for the
wrongful ^ death of a fetus that was injured and died before it was viable ,''''^ and
some have expressly disapproved it,'^^ apparently on the view that until the fetus
reaches a stage when it is capable of independent existence, (1) it cannot be
considered a "person" under the wrongful death statutes, (2) there is no assur-
ance that it would ever have attained this state in development had the defen-
dant not injured it, and (3) as a matter of proof, it is difficult even to be
sure (at least prior to quickening) that there was a "live" being at all which
was caused to die by the defendant's act and not otherwise .•'•"
Courts of equity will act to protect at least some of the interests of the
fetus, apparently without regard to the stage of gestation, for example, the
conservation of property to which it is entitled upon its birth.''* A father's
statutory obligation to support his children has been read to entitle an unborn
child to be represented by a guardian appointed to bring an action against the
father to compel support prior to birth. 'i' The cases on the appointment of a
guardian to consent to a transfusion for a pregnant women to save her life and
that of her child all involve fetuses that were viable and indeed near term, '2°
but if a well-defined right of a previable fetus (to be protected against phy-
sical or financial injury) can be indentified, it is probable that the courts
would be willing to appoint a guardian to conserve and protect that interest on
behalf of the fetus.
2. Consent. This presents the question of consent since the balancing
of the nonviable fetus' interests will depend on whose interests are being
asserted on the other side. Even more than with the' viable fetus in utero, the
mother's right to take steps which will lead to the destruction of the fetus
suggests that its interests are only weak ones; whether they are viewed as being
outweighed by the mother's or whether they should be seen instead as being non-
existent in the face of hers is a moot question. State intervention to promote
the well-being of a nonviable fetus ex utero raises policy issues but is prob-
ably constitutional,^^' but dictation to the mother and physician of medical
decisions on the grounds of protection of the nonviable fetus in utero has been
found unconstitutional }^^
There are, however, two difficult consent issues which remain regarding
fetal research. The first is whether the woman's control over her own body,
which allows her to participate or refuse experimental interventions which
affect her as the subject of research and may incidentally affect her fetus,
should be balanced by any separate consent from someone else in the case of
research which is intended primarily to affect the fetus as a subject. The
physical relationship of mother and fetus makes it plain that her consent must
be required for all experiments on her fetus, except perhaps for a lifesaving
procedure which is experimental but nevertheless likely to give needed benefit
to the fetus. When the woman is willing to consent, there may be two grounds
on which no further consent need be sought. One would be that the nonviable
fetus, lacking a legal personality, need not be represented. The teaching of
the civil law, however, would seem to be that the state may recognize a poten-
tial person and protect it in certain ways. The second ground for not requiring
"fetal consent" as such is that the mother's right of decision, recognized in
Roe v. Wade, to destroy the fetus for her own, possibly selfish reasons, is
broad enough to permit her to permit it to be used in research that is less
harmful than total destruction and is supported by legitimate scientific reasons.
Yet this points to the second consent issue: whether the consent to parti-
cipate in research can be tied to an agreement to abort. Without such agreement,
the law's concern that harm not be done to a person has not been met; furthermore
other parties, such as the father and officials of state welfare agencies, who
have an interest in the potential child's health and life after birth and obli-
gations to provide it with necessary care, would seem to have legitimate grounds
for insisting that their interests be protected. Yet an agreement to abort would
probably be unenforceable, as against public policy and in violation of the preg-
nant woman's rights of self-decision under Roe v. Wade.
There is no easy way out of the conundrum created once one recognizes the
nonviable fetus in utero as a being of some sort (though not yet a person) for
whom permission must be given for use in an experiment. To locate the authority
with the pregnant woman will not satisfy some because of her potential conflict
of interest; yet to locate it with another person not only creates problems of
great substantive and procedural complexity but would in all probability be
found to be unconstitutional in the event that the other person were to try and
keep the woman from acting in the way she wanted to. One partial "solution" to
the dilemma is suggested by the Massachusetts statute; it provides that research
may take place on a fetus which is "not the subject of a planned abortion" and
that a statement signed by the women "that she was not planning an abortion"
supplies conclusive evidence on the point .^^■' While this might permit a fetus
that v/as to be carried to term to be exposed to risk/^* and thus contradict the
law's solicitude for a sound mind and body at birth, it can be seen instead as
asking the pregnant woman (as well as the physician-investigator) : "Are you
willing to experiment in this way and with these risks on a fetus which will be
born?" Thus, it attempts to use maternal concern as a protection against exploi-
tation and unwarranted risks, without precluding the subsequent performance of an
abortion if there is a change of mind or if experience (with other fetuses that
were carried to term) shows that the risks were greater than had reasonably been
anticipated. In some cases this arrangement might be just a charade by women who
intended all along to abort, but it might prompt caution and greater protection
of the fetus as a research subject in other cases and it would provide a very
valuable safeguard in those cases in which a woman did actually change her mind
and not have an abortion.
Unfortunately, if such a statute were actually used to keep a woman who
declared that she was planning an abortion from volunteering for an experiment
it would probably be held to exceed the state's legitimate authority to inter-
vene in the private decisions of women and their physicians. The great deference
which the Supreme Court showed to women's right to decide about what medical
steps are in their own best interests would probably extend to a desire not to
"waste" a pregnancy if it could help medical science. Of course, it is just this
factor which may amount to the conflict of interest that is argued to disqualify
maternal decisionmaking about fetal participation in research. A Massachusetts-
type limitation would raise fewer questions (although it would not be immune from
attack) if it were part of the conditions governing the award of government
grants and contracts. Neither women nor their physicians can insist that the
government fund certain types of research, or permit everyone who wants to parti-
cipate to do so.
Nothing is included here on the elements of the consenting process itself,
whether the person giving permission is the mother or someone else. These matters
are taken up in another recent publication .^^^
3. Compensation. Although the scope of this memorandum was limited to the
question of what the law says about the interests implicated in fetal experimen-
tation, one comment should be made about another function of the law. The rules
of the criminal and civil law have been described largely in terms of thfe
interests they articulate and the means by which they attempt to affect behavior,
through deterrence of conduct which is harmful to those interests or through
active intervention (as by a court-appointed guardian) . Once harm occurs, how-
ever, the law also determines how the burdens imposed by that harm are to be
borne. It would therefore seem imperative for the National Commission to define
the types of conduct which would cause the harm suffered by fetal subjects to be
shifted from them and their parents to the persons or agencies sponsoring the
research or perhaps to society at large, if we are all the beneficiaries of the
research. Since there is no way that the fetus can itself consent to the
research, the usual standard — that the losses are shifted only if they are attrib-
utable to the investigator's negligence — does not provide adequate compensation
13-30
or take fair account of who it was who decided to run the risks in the first
place. On the other hand, the adoption of a strict liability standard makfes
more crucial the problem of determining whether the handicaps of the fetus were
the product of the research (and hence compensable) rather than of other causes
(not compensable) , and it also highlights the inequity of fully compensating an
injured fetal subject while other fetuses who suffer from naturally occurring
handicaps of the same or great degree are often not provided with adequate
medical care, much less "compensation."
REFERENCES
For example, any official attempt to limit the publication of the results of
fetal experiments conducted in violation of the law would run into first
amendment problems.
410 U.S. 113 (1973) .
Such disciplinary action may become a matter of legal interest if, for exam-
ple, question is raised whether it comports with the procedural requirements
imposed on bodies which impose penalties, particularly with state sanction.
See, e.g., Philipson, Sabath, and Charles, "Transplacental Passage of Erythro-
mycin and Clindamycin," New England Journal of Medicine 288:1219, 1973, the
legal sequelae of which are discussed more fully below.
If it is thought that such things as the amniotic fluid and placenta relate to
the woman's body, rather than being "tissues . . . fluids and other portions
of [the fetus'] body," then these would be regarded like any other anatomical
specimen and her consent would be necessary for their use in a research pro-
cedure. See The Institutional Guide to DHEW Policy on Protection of Human
Subjects 3, 1971.
"Availability" is not further defined, but would seem to be subject to the
"good faith" requirement of §7 (c) .
Ky. Gen. Ann. Acts, ch. 255, §13 (1974); La. Rev. Stat. Ann. §14:87.2 (Supp.
1974); Me. Rev. Stat. Ann., tit. 22, §§1574-76 (Supp. 1974); Minn. Sess.
Laws, ch. 562, §2 (1973); Mo. 77th Gen. Ass., 2d Reg. Sess., Act 76, §6(3)
(1974); Mont. Rev. Codes Ann. §94-5-617 (Supp. 1974); Neb. Rev. Stat. §28-4,
161 (Supp. 1973); and Pa. Sess. Laws 1974, Act 209, §5 (1974). The Louisi-
ana, Maine and Pennsylvania statutes make fetuses "live born" or "born
alive" impermissible subjects of human experimentation, but it seems prob-
able that the statutes would be construed not to prohibit research with a
live born fetus which subsequently died and was given for research pursuant
to the UAGA.
"Fetal remains" is defined as "a lifeless product of conception regardless of
the duration of pregnancy." Cal. Health & Safety Code §25956 (Supp. 1974).
In criminal, although not in civil, actions, a written statement authorizing
the use of the fetus in research from the mother (at least 18 years old) is
"conclusively presumed" to constitute the necessary consent. The consent
also permits the "transfer of the dead fetus" to the site of the experiment.
Although the sale of a fetus "for a use which is in violation of the pro-
visions of" the statute is illegal, and the cost of an abortion may not be
REFERENCES (Continued)
9. (cont.) reduced in whole or in part because the woman has agreed to give "the
fetal remains" for research, the statute does not appear to prohibit out-
right payment to a woman for a dead fetus to be used consonant with the
statutory provisions. Mass. 1974 Reg. Sess. Laws, ch. 421 (adding §12 J to
Ch. 112 of the General Laws) .
10. S.D. Compiled Laws Ann. §34-23A-17 (Supp. 1974).
11. The Illinois statute requires an "analysis and tissue report" by a pathologist
on "all tissue removed at the time of abortion" as a "matter of record in
all cases," while prohibiting "exploitation of or experimentation with" such
tissue. 111. 1973 Laws, Pub. Act 78-225, §8. In Indiana, pathological exam-
inations are permitted but not required; no experimentation is permitted
"nor shall any fetus so aborted be transported out of this state for experi-
mental purposes." Ind. Ann. Stat. §10-112 (Burns Supp. 1974).
12. Ohio Rev. Code Ann. §2919.14 (Page's Legis. Supp. 1974).
13. Mo. 77th Gen. Ass., 2d Reg. Sess., Act 76, §2(1) (1974).
14. This follows for two reasons. First, the statutes typically permit persons
to make use of a body if they are "lawfully authorized" to do so. Second,
the UAGA, which is a recent enactment, would appear to supersede any incon-
sistent prior legislation. It specifically provides, in section 7(c), that
a person acting in good faith accord with the Act is not subject to prose-
cution in any criminal proceeding.
15. See note 4 supra. Despite the women's consent to undergo the experiments
themselves, permission was not asked nor given to study the aborted fetuses.
Culliton, "Grave Robbing: The Charge Against Four from Boston City Hospital,
Science 186:420, 1974.
16. The Massachusetts Violation of Sepulture Statute provides:
Whoever, not being lawfully authorized by the proper authorities,
wilfully digs up, disinters, removes or conveys away a human body,
or the remains thereof, or knowingly aids in such disinterment,
removal or conveying away, and whoever is accessory thereto either
before or after the fact, shall be punished by imprisonment in the
state prison for not more than 3 years or in jail for not more
than 2-1/2 years or by a fine of not more than two thousand dol-
lars .
Mass. Gen. Laws Ann., ch. 272, §71 (1968).
17. 36 Mass. (19 Pick.) 304 (1837).
13-33
REFERENCES (Continued)
18. One case suggests that "human body or remains" will be narrowly construed.
In State v. Glass, 27 Ohio App.2d 214, 273 N.E.2d 893 (1971), a real
estate developer who had purchased a tract of approximately 50 acres, the
deed to which excepted a cemetery about 1/7 of an acre in size containing
4 graves about 125 years old, nevertheless ordered the leveling of the
cemetery and employed a licensed undertaker to move the bodies. Defendant
was arrested and convicted under a statute providing for the removal of
gravestones and under the Ohio grave robbing statute. His conviction was
affirmed as to the removal of the gravestones, but reversed under the
grave robbing statute, the court holding that excavation ceases to be a
grave under the statute when the human remains originally placed therein
have decomposed to such a degree that they no longer meet the definition
of a corpse or a dead body. The court also said the statute only applied
to grave robbers, ghouls and like persons who have a nefarious purpose in
disturbing the excavation.
19. Fla. Stat. Ann. §872.01 (Supp. 1974).
20. See, e.g.. Ad Hoc Committee of the Harvard Medical School to Examine the
Definition of Brain Death, "A Definition of Irreversible Coma," Journal of
the American Medical Association 205:337, 1968; "When Is A Patient Dead?"
Journal of the American Medical Association 204:1000, 1968 (editorial);
Curran, "Legal and Medical Death — Kansas Takes the First Step," New England
Journal of Medicine 284:260, 1971.
21. See Cal. Health & Safety Code §§7180-82 (Supp. 1975); Kan. Stat. Ann. §77-202
(Supp. 1974); Maryland Sess. Laws ch. 693 (1972). The American Bar Associ-
ation recently adopted a policy statement, defining death as "irreversible
total cessation of brain function," which they recommended for considera-
tion by states adopting definitions and by the National Conference on Uniform
State Laws. See 43 U.S.L.W. 2362 (1975). At the time the UAGA was drafted,
its authors did not believe that a definition of death need be included;
under section 7(b) the "time of death" was left to the "physician who attends
the donor at his death or, if none, the physician who certifies death."
22. See, e.g., Capron and Kass, "A Statutory Definition of the Standards for
Determining Human Death: An Appraisal and a Proposal," University of
Pennsylvania Law Review 121:87, 1972. See also note 32 infra.
23. See, e.g., Colo. Rev. Stat. Ann. §66-8-2(6) (Cum. Supp. 1967); Conn. Gen. Stat.
Ann. §7-60 (1958); Fla. Stat. Ann. §382.071 (1973); Ga. Code Ann. §88-1702 (f)
(1971); 111. Ann. Stat. ch. 111-1/2, §73-1 (Smith-Hurd Supp. 1974); Mass.
Ann. Laws ch. 46, §94 (1973); N.Y. Pub. Health Law §4160 (McKinney 1971);
Pa. Stat. Ann. tit. 35, §450.105 (Supp. 1975); Wash. Rev. Code Ann.
§70.58.150 (1961) .
24. See, e.g., Colo. Rev. Stat. Ann. §66-8-10 (Cum. Supp. 1967).
13-34
REFERENCES (Continued)
25. See, e.g., N.J. Stat. Ann. §26:6-11 (Supp. 1974) and Pa. Stat. Ann. tit. 35,
§450.501 (Supp. 1975) (after 16 weeks gestation).
26. See, e.g., Cal. Health & Safety Code §10175 (1964); Conn. Gen. Stat. Ann.
§7-60 (1972); Fla. Stat. Ann. §382.071 (1973); Mass. Ann. Laws ch. 46
§9A (1973); Mich. Comp. Laws Ann. §326.15 (1967); Wash. Rev. Code Ann.
§70.58.160 (1961). Illinois, in addition to the certificate of fetal
death for post-20 week fetuses. 111. Ann. Stat. ch. 111-1/2, §73-20
(Smith-Hurd Supp. 1974) , also provides for a special report of each
abortion performed prior to 20 weeks. 111. Ann. Stat. ch. 38, §81-15
(Smith-Hurd Supp. 1974) .
27. See, e.g., Ga. Code Ann. §88-1716 (1971) and N.Y. Pub. Health Law §4160
(McKinney 1971) .
28. Examples of birth certificate related statutes defining "live birth" are
111. Ann. Stat. ch. 111-1/2, §73-1(5) (Smith-Hurd Supp. 1974); Minn. Stat.
Ann. §144.151 (1970); N.Y. Pub. Health Law §4130 (McKinney Supp. 1974);
Pa. Stat. Ann. tit. 35, §450.105(3) (1964). In addition, a number of the
anti-fetal research statutes passed in the last two years also include a
definition of "live born," which adopts the usual indicia of life. See,
La. Rev. Stat. Ann. §14:87.2 (Supp. 1974) and Me. Rev. Stat. Ann., tit. 22,
§1576 (Supp. 1974); see also note 7 supra. Statutes in a number of states,
such as California, Connecticut and Florida, use the term "live birth"
without definition.
29. See, e.g., Mass. Ann. Laws ch. 46, §9 (1973) and S.D. Compiled Laws Ann.
§34-23A-16 (Supp. 1974).
30. See e.g., Colo. Rev. Stat. Ann. §66-8-5 (1963, repealed and reenacted, Sess.
L. 1967, pp. 1056-63, §§1, 4; "stillborn" is not defined. The District
of Columbia provision on reporting stillbirths after 20 weeks of gesta-
tion as a form of death certification is typical. D.C. Code Ann. §6-301
(Supp. Ill, 1970). Florida, which provides for a "fetal death" certifi-
cate, as discuss.ed in the text above, also requires that certificates be
filed for all "births, deaths, and stillbirths"; in the absence of a
statutory definition it is not clear whether a "stillbirth" is the same
as a fetus born dead or is meant to include a broader category, such as
fetuses born with minimal signs of life who survive only a very brief
period because of their young gestational age. Fla. Stat. Ann. §§382.19 -
382.20 (1967).
31. There is no uniform act proposed for death certification.
32. The investigation of abortions at Boston City Hospital, begun by anti-abortion
furor over the fetal research cited in note 4 supra, was spurred on when
the district attorney's office learned of two dead fetuses in the pathology
department for whom no death certificate had been filed. This led to the
13-35
REFERENCES (Continued)
32. (cont.) indictment of Dr. Kenneth Edelin for manslaughter. Culliton,
"Manslaughter: The Charge against Edelin of Boston City Hospital,"
Science 186:327 (1974).
33. This is the term used in the California statute prohibiting fetal experimen-
tation except research with "fetal remains," which are defined as "a
lifeless product of conception regardless of the duration of pregnancy."
In explaining this term the statute states that a fetus "shall not be
deemed lifeless" unless "there is an absence of a discernible heartbeat."
Cal. Health S Safety Code §25956 (Supp. 1974).
34. This issue of "When Do the Interests Attach?" is explored more fully at
pp. 13-16 to 13-17 infra.
35. Williams, G. , Criminal Law: The General Part, 2d ed. , 1968.
36. The doctrine of intraf amilial immunity, which although criticized still
prevails in most states, would protect the parents from liability to
the fetus for negligent or intentional injuries.
37. The leading case is Regina v. Senior, [1899] 1 Q.B. 283, in which a father
was convicted of manslaughter for declining to provide medical care for
his 8- or 9-month-old infant based on his religious beliefs. It has been
followed in this country. See, e.g., Craig v. State, 220 Md. 590, 155
A. 2d 684 (1959). See also Stehr v. State, 92 Neb. 755, 139 N.W. 676,
aff'd on rehearing, 142 N.W. 670 (1913) (upholding manslaughter convic-
tions of father who attempted to excuse his negligent failure to care for
his 2-year-old stepson on the grounds that as a poor immigrant he was
unable to procure medical assistance). But see Regina v. Knights, 175
Eng. Rep. 952 (1860) , which involved the failure of a woman in labor to
obtain the necessary assistance, wherefore her child died; the trial
judge's dismissal suggests that there are circumstances in which conduct
though unreasonable as a general rule is excused by the actor's condition.
38. When the harm threatened is great the state may not wait for it to occur but
instead may intervene to override a parental choice that falls outside the
bounds of "reasonableness" in the society at large. See, e.g., Johovah ' s
Witnesses v. Kings County Hosp., 278 F.Supp. 488 (W.D. Wash. 1967), aff'd,
390 U.S. 598 (1968) .
39. See Robertson, "Involuntary Euthanasia of Defective Newborns: A Legal
Analysis," Stanford Law Review 27:213,235-37, 1975.
40. The term "nonbenef icial experiment," which is used here for this category,
may be somewhat confusing since it might suggest that no good will come to
anyone from the research. The term is meant, on the contrary, to suggest
that despite the potential benefits to others (which may be great or small,
but if lacking entirely would mean that the research should not be done)
the subject does not stand to gain anything (such as an improvement in
13-36
REFERENCES (Continued)
40. (cont.) diagnosis or therapy) as a result of participating. It is assumed
that there is another, complementary category of experiments which can be
said to be "beneficial" to their patient-subjects. Since experimentation
is involved, the risks and benefits are uncertain (to a greater degree
than the uncertainty which is said to attend each use of even well estab-
lished medical techniques) , but the experiment may still be termed
"beneficial" in the intent of the investigator, a factor which the law
regards seriously provided that he is operating within the bounds of
reason and good faith.
41. See Paulsen, "The Legal Frameworlc for Child Protection," Columbia Law Review
66:679, 1956; Robertson, note 39 supra, at 222-24. Neglect statutes tend
to be broadly and vaguely worded and loosely interpreted; while they have
been held to cover parents who do not provide proper medical care, see,
e.g., Matthews v. State, 240 Miss. 189, 126 So. 2d 245 (1961) (neglecting
to provide digitalis for child left in nursery) , and while some specifi-
cally punish the failure to furnish medical assistance, see, e.g., N.J.
Stats. §9:6-3 (West 1960), they are certainly open to due process objec-
tions and many are probably unconstitutional.
42. The doctrine of "informed consent," which grew out of the law of assault and
battery, is the most important example of this concern in the tort rules
applicable to medical experimentation. It proceeds from the premise that
a person's interests in autonomy, self-determination and privacy are such
that he or she has suffered a compensable dignitary harm if a physician
does (or threatens to do) anything to them without permission, even if no
physical harm is caused thereby. See generally, Katz, J. with assistance
of Capron, A., and Glass, E., Experimentation with Human Beings 521-724,
1972.
43. Curran and Beecher, "Experimentation in Children," Journal of the American
Medical Association 210:77, 1969.
44. See generally Capron, "Legal Considerations Affecting Clinical Pharmaco-
logical Studies in Children," Clinical Research 21:141,143-44, 1972.
45. Nielsen v. Regents of the Univ. of California, No. 665-049 (Super. Ct. S.F.
Co., filed Sept. 11, 1973).
46. See notes 7-13 supra for citations.
47. California, Louisiana, Massachusetts, Minnesota, Missouri, Montana and
Pennsylvania. The Minnesota statute contains the additional proviso, con-
gruent with the common law view but not otherwise spelled out, that research
is also permissible if "verifiable scientific evidence has shown [it] to be
harmless to the conceptus . " Minn. Sess. Laws, ch. 562, §2(1973).
13-37
REFERENCES (Continued)
48. The Ohio statute, for example, flatly declares that "No person shall experi-
ment upon . . . the product of human conception which is aborted." Ohio
Rev. Code Ann. §2919.14 (Page's Legis. Supp. 1974). But this comes immedi-
ately after a section (§2919.13) creating the crime of "abortion manslaughter'
which consists of failing "to take the measures required by the exercise of
medical judgment in light of the attending circumstances to preserve the
life of a child who is alive when removed from the uterus of the pregnant
woman." The Illinois, Indiana, Kentucky, Maine and Nebraska statutes also
require measures be taken to save viable abortuses .
49. The Maine statute, which would appear to ban all experimental interventions
with a living aborted fetus, was plainly directed only at nonbenef icial
■ :■ research since it punishes anyone who "shall use, transfer, distribute
or give away" a fetus "for scientific experimentation or for any form of
experimentation." Me. Rev. Stat. Ann. tit. 22, §157 (Supp. 1974). The
Illinois ("exploitation of or experimentation with"), Indiana ("transported
out of this state"), Kentucky ("sell, transfer, distribute or give away
any live or viable child or permits such child to be used for any form of
experimentation"), Nebraska ("sell, transfer, distribute, or give away"),
and Ohio ("experiment upon or sell") statutes are subject to a similar
construction.
50. 111. Ann. Stat. ch. 111-1/2, §73-1(5) (Smith-Hurd Supp. 1974). See note 28
supra for additional statutes.
51. Harris v. State, 28 Tex. App. 308, 12 S.W. 1102 (1889); Evans v. People,
49 N.Y. 86 (1872) (dictum); but it is not necessary that the umbilical
cord be severed, Jackson v. Comm. , 265 Ky . 295, 96 S.W. 2d 1014 (1936),
nor that the fetus should have breathed. Rex v. Brain, 172 Eng. Rep. 1272
(1834), provided there are other signs of life.
52. Boston Globe, Feb. 15, 1975, at 3, col. 3.
53. Killing a child during delivery is the intentional destruction, during
parturition of the mother, of the vitality of life of a child in a state
of being born and before actual birth, which child would otherwise have
been born alive; provided, however, that the crime of killing a child
during delivery shall not be construed to include any case in which the
death of a child results from the use by a physician of a procedure during
delivery which is necessary to save the life of the child or of the mother
and is used for the express purpose of and with the specific intent of
saving the life of the child or of the mother. La. Rev. Stat. Ann. §14:87.1
(Supp. 1974). In the absence of the "defense" of "best care for the mother,"
such a statute would be unconstitutional on its face. Hodgson v. .Anderson,
378 F.Supp. 1008 (D. Minn. 1974) , appeal dismissed and remanded sub nom.
Spannaus v. Hodgson, 43 U.S.L.W. 3415 (Jan. 27, 1975). Further extensions
of this line of protection of fetal interests are considered in the discus-
sions of the fetus in utero , at pp. 13-20 to 13-21 infra.
13-3f
REFERENCES (Continued)
54. 77 Cal. App.2d 621, 176 P. 2d 92 (1947). Contra State v. Cooper 22 N.J.L.
52 (1849) (not murder to Pcill a child before it is born, "even though it
be killed in the very process of delivery") .
55. 77 Cal. App.2d at 627, 176 P. 2d at 95. In a more recent opinion, Keeler v.
Superior Court of Amador County, 2 Cal . 3d 619, 87 Cal. Rptr. 481, 470 P. 2d
617 (1970) , the California Supreme Court reiterated the common law rule
that an infant cannot be the subject of homicide \inless it has been born
alive. It recognized the Chavez dictum that homicide could encompass a
living baby "where in the natural course of events a birth which is already
started would naturally be successfully completed," id., at 537, 87 Cal.
Rptr. 492, 470 P. 2d at 628 (italics in original), quoting 77 Cal. App.2d
at 626, 176 P. 2d at 94, but found that this limited rule had no application
to the case before it, in which an estranged husband had caused the death
in utero of a viable 35-week fetus by "stomping" on his ex-wife's abdomen.
In apparent reaction to this decision, the California legislature amended
the murder statute to include the killing of a fetus, unless it occurred
(a) during a therapeutic abortion, (b) as a result of medical intervention
where childbirth threatened the mother's life, or (c) with the mother's
consent. Cal. Pen. Code §187 (West Supp. 1975), as amended by Stats. 1970,
c. 1311, p. 2440, §1. The failure of the legislature to amend the man-
slaughter statute means that the common law rule of "live birth" continues
to apply to that offense. People v. Carlson, 37 Cal. App.3d 349, 112 Cal.
Rptr. 321 (1974) .
56. State v. Osmus , 73 Wyo. 183, 276 P. 2d 469 (1954). Professor John A. Robert-
son argues that where the need for medical care is clear, "failure to
obtain care that leads to the infant's death should be culpable," and
cites State v. Shepherd, 255 Iowa 1218, 124 N.W.2d 712 (1963), as embodying
a "better approach" to the question of whether liability flows from an
unreasonable railure to seek medical care when birth is imminent. Robert-
son, supra note 39, at 218 n. 34.
57. This duty is recognized in both the criminal law, see LaFave, W. , and
Scott, A., Handbook of Criminal Law 186, 1972; Holmes, 0., The Common Law
278, 1881 ("If a surgeon from benevolence cuts the umbilical cord of a
new-born child he cannot stop there and watch the patient bleed to death.
It would be murder wilfully to allow death to come to pass in that way.");
and in the civil, cf. Depue v. Flateau, 100 Minn. 299, 111 N.W. 1 (1907).
58. See, e.g., in re Kershaw, 5 Rob. 488 (La. 1843).
59. See, e.g., in re Principal's Guardianship, 101 Cal. App. 669, 282 P. 26 (1929)
Succession of Simkin, 164 La. 223, 113 So. 825 (1927).
60. The father, by explicitly agreeing to the abortion, may place himself in the
same category as the mother, but since he cannot under Roe v. Wade forbid
her from undertaking the abortion his mere acquiescence should not be taken
13-39
REFERENCES (Continued)
as sufficient to deny him the rights he would otherwise enjoy concerning
the fetus. See, e.g., Coe v. Gerstein, 373 F.Supp. 695 (S.D. Fla. 1973)
appeal dismissed, 417 U.S. 279 (1974) (requiring spousal consent held
unconstitutional) .
61. The neglect laws typically provide for a means for a parent voluntarily to
give his or her rights and obligations over to the public welfare author-
ities.
62. That is not to say that the process of decisionmaking, including the involve-
ment of the judiciary in determining neglect, is easy or painless. The
situation in which this issue has arisen has thus far not involved proposed
experimentation on a neonate but parental refusal of "ordinary" surgery
needed by a defective infant to survive. The parents in one recent case,
Maine Medical Center v. Houle, Civil No. 74-145 (Super. Ct., Cumberland Co.
Feb. 14, 1974) (parents' refusal constituted neglect), expressed great
anguish at being brought into the legal system and having the decision
taken away from them (the baby died following the surgery) . Auerback,
"Court-Ruled Surgery Fails to Save Baby," Washington Post, Feb. 25, 1974,
§A at 1, col. 1.
63. La. Rev. Stat. Ann. §§13:1569, :1570 (Supp. 1974).
64. Mo. 77th Gen. Ass., 2d Reg. Sess., Act 76, §7 (1974).
65. It would, of course, apply to the rarer case of the abortion of a previable
fetus who lived for a short time; this is discussed below.
66. Mont. Rev. Codes Ann. §94-5-617 (2) (b) (Supp. 1974).
67. Ky. Rev. Stats. §199.600 (Supp. 1974). -
68. Ind. Ann. Stat. §10-113 (Burn's Supp. 1974).
69. S.D. Compiled Laws Ann. §34-24A-18 (Supp. 1974).
70. The Minnesota abortion statute, which is similar to the Montana law described
in the text, provided that a live born child resulting from an abortion
shall become a ward of the state unless the abortion was performed to save
the life of the woman or the child or one or both parents agree within 30
days to accept the parental rights and responsibilities; it has been held
unconstitutional and enjoined. Hodgson v. Anderson, 378 F.Supp. 1008
(D. Minn. 1974) , appeal dismissed and remanded sub nam. Spannaus v. Hodgson,
43 U.S.L.W. 3415 (Jan. 27, 1975). The Missouri provision described in the
text (accompanying note 64) was upheld by a three judge district court but
stayed pending appeal by the Supreme Court, F.Supp. (E.D. Mo. 1974) , 43
U.S.L.W. 3451 (Feb. 18, 1975).
The problems with the revocation of parental rights over an area as funda-
mental as control and custody of a child, see Wisconsin v. Yoder, 406 U.S.
13-40
REFERENCES (Continued)
205 (1972); Eisenstadt v. Baird, 405 U.S. 438 (1972); Pierce v. Society of
Sisters, 268 U.S. 510 (1925), are exacerbated when the revocation is made
automatic; it would seem to be a violation of due process to act without
a clear showing of actual or impending neglect and only on the basis of
a presumption. See Cleveland Board of Education v. LaFleur, 414 U.S. 632
(1974) (conclusive presumption that school teacher is physically unable
to work after fifth or sixth month of pregnancy held unconstitutional) .
As the Court, in holding unconstitutional an irrebutable presumption that
unmarried fathers are incompetent to raise their children, stated in Stanley
V. Illinois, 405 U.S. 645, 654 (1972):
It may be, as the State insists, that most unmarried fathers are
unsuitable and neglectful parents. It may also be that Stanley
is such a parent and that his children should be placed in other
hands. But all unmarried fathers are not in this category; some
are wholly suited to have custody of their children. (Footnotes
omitted. )
Similarly, some mothers who abort fetuses that then survive may be unsuitable
and neglectful, so that their infants should be placed into the state's hands.
But it violates due process so to presume for all such mothers. As Stanley
also holds, the speed and efficiency of a presumption are not sufficient to
redeem it. Idem, at 656.
71. Keeler v. Superior Court of Amado Co., 2 Cal. 3d 619, 87 Cal . Rptr. 481, 470
P. 2d 617 (1970) (unborn, viable fetus not a person within meaning of murder
statute); State v. Dickinson, 23 Ohio App.2d 259, 52 Ohio Ops. 2d 414, 263
N.E.2d 253 (1970) (unborn, viable fetus not a person within meaning of
vehicular homicide statute) . See also note 54 supra.
72. See note 5 3 supra.
73. Of course. Roe v. Wade, 410 U.S. 113 (1973), is always subject to revision
or even reversal, either through a constitutional amendment or through
subsequent decisions of the Court (which approved it by an 7-2 majority) .
For the moment, however, it must be regarded by the National Commission,
in any recommendations it makes to the Secretary, or by the national and
state legislatures, in any laws they pass, as setting forth the constitu-
tional limits within which fetal experimentation may be regulated.
74. There have been various definitions of "quickening" used by the common law
over the years, both in abortion law (since causing an abortion before
quickening was not regarded as a punishable offense, but after quickening
it was a misdemeanor) and under the feticide statutes. Whenever it is
assumed to occur (from 5 weeks to 18 weeks, depending on the authority) ,
quickening means that the fetus is felt to move; this was significant
because (1) it showed that a live being, capable of being killed, was in
existence, and (2) it was associated with the theological concept of the
soul entering the body. In any case, this point of development almost
certainly occurs before the fetus is "viable" given present medical tech-
nology.
13-41
REFERENCES (Continued)
75. "Malice" as used in the law of homicide is a term of art, not used in its
usual sense of "ill will," but meaning that the actor has manifested the
specific intent to cause death or grievous bodily harm or otherwise to
commit a felony.
76. See, e.g., Passley v. State, 194 Ga. 327, 21 S.E.2d 230 (1942) (feticide
conviction reversed because indictment was defective in failing to allege
necessary intent); State v. Harness, 280 S.W.2d 11 (Mo. 1955) (manslaughter
conviction reversed because evidence that defendant had killed unborn child
was insufficient to prove that he acted with malicious intent to kill the
pregnant woman). Cf. Williams v. State, 34 Fla. 217, 15 So. 760 (1894)
(affirming manslaughter conviction under feticide statute on grounds that
defendant's unprovoked and cruel assault upon his wife with a club and
his threats to kill her were sufficient evidence of premeditation of mur-
der; statute deemed it manslaughter if fetus died from injury which would
have been murder if it had resulted in death of the mother) .
77. Were he to bring about the miscarriage of the fetus intentionally he would
probably still not be liable under the feticide statute unless he also
assaulted the woman and tried to kill her; he would, however, probably be
guilty of criminal abortion, which is defined in many states to include
the performance of an abortion without the consent of the woman.
78. See Clark v. State, 117 Ala. 1, 23 So. 671 (1898); Morgan v. State, 148 Tenn.
417, 256 S.W. 433 (1923); Abrams v. Foshee, 3 Iowa 274 (1856) (dictum).
79. Anderson, Wharton's Criminal Law and Procedure 435, 1957.
80. Roe V. Wade 410 U.S. 113, 153 (1973).
81. The British Abortion Act of 1967 and the pre-Roe Uniform Abortion Act
(proposed by the Conference of Commissioners on Uniform State Laws and
endorsed by the American Bar Association) both permitted abortion when
there was substantial risk that the child if born would suffer from a
serious defect. See also Smith v. Brennan, 31 N.J. 353, 364, 157 A. 2d
497, 503 (1960) ("a legal right to begin life with a sound mind and body").
But see Gleitman v. Cosgrove , 49 N.J. 22, 237 A. 2d 689 (1967) (holding no
cognizable claim for physician's failure to warn parents of prenatal
injuries which would have led them to abort the child) , criticized in
Capron, "Informed Decisionmaking in Genetic Counseling: A Dissent to the
'Wrongful Life' Debate," Ind . L.J. 48:581,594-602, 1973.
82. Roe V. Wade, 410 U.S. 113, 161-62 (1973).
83. This view was established by Justice Holmes in Dietrich v. Northampton,
138 Mass. 14 (1884) .
84. O'Neill v. Morse, 385 Mich. 130, 135, 188 N.W.2d 785 (1971).
13-42
REFERENCES (Continued)
85. Norman v. Murphy, 124 Cal. App.2d 95, 268 P. 2d 178 (1954); Stokes v. Liberty
Mut. Ins. Co., 213 So. 2d 695 (Fla. 1968); McKillip v. Zimmerman, 191 N.W.
2d 706 (Iowa 1971); Leccese v. McDonough , 279 N.E.2d 339 (Mass. 1972);
Action V. Shields, 386 S.W.2d 363 (Mo. 1965); Drabbels v. Skelly Oil Co.,
155 Neb. 17, 50 N.W. 2d 229 (1951); Graf v. Taggert, 43 N.J. 303, 204 A. 2d
140 (1964); Endresz v. Friedburg, 24 N.Y.2d 478, 248 N.E.2d 901, 301 N.Y.S.
2d 65 (1969); Gay v. Thompson, 266 N.C. 394, 146 S.E.2d 425 (1966); Padillo
V. Zirod, 424 P. 2d 16 (Okla. 1967); Caroll v. Skloff, 415 Pa. 47, 202 A. 2d
9 (1964); Durrett v. Owens, 212 Tenn. 614, 371 S.W.2d 433 (1963); Lawrence
V. Craven Tire Co., 210 Va. 138, 169 S.E.2d 440 (1969). C£. Mace v. Jung,
210 F.Supp. 706 (D. Alas. 1962) (recovery for nonviable fetus denied).
86. Endresz v. Friedburg, 24 N.Y.2d 478, 485, 248 N.E.2d 901, 905, 301 N.Y.S. 2d
65, 70 (1969), quoting Keyes v. Construction Service, 340 Mass. 633, 636,
165 N.E.2d 912, 915 (1960). . . ^ .
87. Eich V. Town of Gulf Shores, 300 So. 2d 354 (Ala. 1974); Hatala v. Markiewicz,
20 Conn.Supp. 358, 224 A. 2d 406 (1966); Worgan v. Greggo and Ferrara, Inc.,
50 Del. 258, 128 A. 2d 557 (1956); Simmons v. Howard Univ., 323 F.Supp. 256
(D.D.C. 1971); Porter v. Lassiter, 91 Ga.App. 712, 87 S.E.2d 100 (1955);
Christafogeorgis v. Brandenburg, 55 111. 368, 304 N.E.2d 88 (1974); Britt
V. Sears, 277 N.E.2d 20 (Ind. ct. App. 1971); Hale v. Marrion, 189 Kan.
134, 368 P. 2d 1 (1962); Mitchell v. Couch, 285 S.W.2d 901 (1955); Valence
V. Louisiana Power and Light Co., 50 So. 2d 847 (La. Ct. App. 1951);
State ex rel . Odham v. Sherman, 234 Md. 179, 198 A. 2d 71 (1964); O'Neill
V. Morse, 385 Mich. 130, 188 N.W. 2d 785 (1971); Verkennes v. Corniea, 229
Minn. 365, 38 N.W. 2d 838 (1949); Rainey v. Horn, 221 Miss. 269, 72 So. 2d
434 (1954); White v. Yup, 458 P. 2d 617 (Nev. 1969); Poliquin v. MacDonald,
101 N.H. 104, 135 A. 2d 249 (1957); Stidam v. Ashmore , 109 Ohio App. 431,
167 N.E.2d 106 (1959); Libbee v. Permanente Clinic, 518 P. 2d 636 (Ore.
1974); Fowler v. Woodward, 244 S.C. 608, 138 S.E.2d 42 (1964); Baldwin v.
Butcher, 184 S.E.2d 428 (W. Va. 1971); Kwaterski v. State Farm Mut. Auto.
Ins. Co., 34 Wis. 2d 14, 148 N.W. 2d 107 (1967).
88. Roe V. Wade, 410 U.S. 113, 152 (1973), citing Louisell, "Abortion, The
Practice of Medicine, and the Due Process of Law," U.C.L.A. Law Review
16:233,235-38 (1969); Note, Iowa Law Review 55:994,999-1000, 1971; Note,
"The Law and the Unborn Child," Notre Dame Law 46:349,351-53, 1971.
89. Roe V. Wade, 410 U.S. 113, 163 (1973). ' -
90. Idem, at 153.
91. Since the unborn fetus is not a "person" legally, there can be no question
of depriving it of the equal protection of the laws in those jurisdictions
that do not impose criminal or civil liability on persons who injure a
viable fetus which dies in utero while imposing such liability if the same
acts caused death in a live born person.
REFERENCES (Continued)
92. The criminal law is sterner on this point than the civil. It is murder
intentionally to extinguish the last spark of life even in a person who
has been mortally wounded by someone else. The civil law takes a wider
view of causation. An action is said to be a legal cause of harm to
another if it is a substantial factor in bringing about the harm; it may
be a substantial factor even if the harm would have been sustained with-
out it, so long as both the action in question and the other causes are
actively operating to the same result. See Restatement, Torts 2d, §§431-32.
Because it enjoys greater flexibility than the criminal law (judgments from
1<? on up rather than simply "guilty" or "not guilty") , tort law can say
that a person's conduct caused the death of a dying man and still award
only a small damage award because the amount of life left was very short.
93. It may be, for example, that society wishes to prevent what it sees as harm
to fetuses because of the pain that the perception of such harm brings to
its viewers. While the protection of such interests is a dubious rationale
for preventing people from doing things which may hurt themselves but not
harm others physically (e.g., "victimless" crimes), it does provide the
justification for other kinds of legal constraints on people's conduct
toward other people or things (e.g., statutes on humane treatment of
animals .
94. See notes 35-41 supra and accompanying text.
95. The Missouri statute makes it manslaughter if the fetus died because the
physician (or others) failed to use the same "degree of professional
skill, care and diligence" to keep alive any abortus "as would be
required ... in order to preserve the life and health of any fetus
intended to be born." Mo. 77th Gen. Ass., 2d Reg. Sess., Act 76, §5(1)
(1974) . The Ohio statute likewise provides that a person performing an
abortion must attempt to "preserve the life of a child who is alive"
and makes no distinction between viable and nonviable fetuses, although
it does leave the steps to "medical judgment." In light of the felony
penalties, a physician's judgment is likely to be very constricted,
however. Ohio Rev. Code Ann. §2919.13 (B) (Page's Legis. Supp. 1974).
96. La. Rev. Stat. Ann. §14:87.2 (Supp. 1974). Of the fourteen statutes on
experimentation with aborted fetuses, see notes 47-49 and accompanying
text, only the California provision might not apply to some previable
fetuses ex utero, namely those which are "lifeless" because they lack
a "discernible heartbeat." Cal. Health & Safety Code §25956 (Supp. 1974).
97. See pp. 13-17 to 13-20 supra.
98. See pp. 13-4 to 13-6 supra.
99. Cf. Note, "Compulsory Removal of Cadaver Organs," Columbia Law Review
69:693, 1969.
100. See Curran, "A Problem of Consent — Kidney Transplantation in Minors,"
New York University Law Review 34:891, 1959.
13-44
REFERENCES (Continued)
101. See, e.g.. In re Martin, Eq. No. 44602 (Cir. Ct. Montgomery Co., Md. ,
Oct. 20, 1972) .
102 . One problem with the transplant cases was that the actual facts and role
relations had to be forced into the adversary process — although it was
only recently that vigorous independent advocacy for the minor donor
became part of the process (in the bone marrow transplant cases in Boston) ,
The resolution of questions like this may better be handled under the
aegis of a European-type judge who plays the active role of inquisitor
rather than a neutral arbiter between litigious adversaries. See gener-
ally Damaska, "Evidentiary Barriers to Conviction and Two Models of
Criminal Procedure," University of Pennsylvania Law Review 121:506,554-86,
1973.
103. See Roe v. Wade, 410 U.S. 113, 132-35 (1973) ("usually from the 16th to the
18th week of pregnancy").
See notes 74-76 supra and accompanying text.
105 . See Means , "The Law of New York Concerning Abortion and the Status of the
Foetus, 1664-1968: A Case for Cessation of Constitutionality," N.Y.L.F.
14:411 (1968); Means, "The Phoenix of Abortional Freedom: Is a Penumbral
or Ninth Amendment Right About to Arise from the Nineteenth-Century Legis-
lative Ashes of a Fourteenth-Century Common-Law Liberty?" N.Y.L.F. 17:335,
1971; Roe V. Wade, 410 U.S. 113, 148-52 and cases cited idem, nn. 48 and
49.
106. Roe V. Wade, 410 U.S. 113, 162 (1973).
107. In re Holthausen's Will, 175 Misc. 1022, 1024, 26 N.Y.S.2d 140, 143 (Sur.
Ct. 1941) . The requirement that the decision benefit the fetus is not
always adhered to. See In re Sankey's Estate, 199 Cal. 391, 249 P. 517
(1926) (posthumous child bound by decree entered against living heirs) .
Cf. Barnett v. Pinkston, 238 Ala. 327, 191 So. 371 (1939) (posthumous
child died a few hours after birth, followed in a few days by its mother
who was its sole heir; her heirs held entitled to remainder of father's
estate which passed through child to mother's estate). .,
108. Louisell, "Abortion, the Practice of Medicine and the Due Process of Law,"
U.C.L.A. Law Review 16:233,237, 1969.
109. See, e.g., Swain v. Bowers, 91 Ind. App. 307, 158 N.E. 598 (1927); Wehrman
V. Farmers' Sav. Bank of Durant, 221 Iowa 249, 259 N.W. 564, rehearing
overruled, 221 Iowa 249, 266 N.W. 290 (1935); Mackie v. Mackie, 230 N.C.
152, 52 S.E.2d 352 (1949). Cf. Roe v. Wade, 410 U.S. 113, 162 (1973)
(perfection of interests of fetus contingent upon live birth) .
13-45
REFERENCES (Continued)
110. Cal. Civ. Code §29 (West 1954) ("in the event of its subsequent birth");
Mich. Stat. Ann. §27.3178 (155) (1962) ("posthumous children"); N.Y. Est.
Powers & Trusts Law §2-1.3, §6-5.7 (McKinney 1967) ("posthumous children");
Okla. Stat. Ann. tit. 15, §15 (1972) ("in the event of its subsequent
birth"); Tex. Prob. Code §66 (1956) ("posthumous children"). Cf. Kimbro
V. Harper, 113 01<1. 46, 238 P. 840 (1925) (statutory construction).
111. It is also worth noting that there is no recorded case of the heir of a
stillborn child claiming rights that had accrued to the child; such a
case would settle the question of whether the fetus is fully "a child"
for estate purposes. Professor Louisell attempts to dismiss the absence
of any such case as a result of "practicalities," Louisell, supra note
108, at 238, n. 24, but the absence only serves to spotlight the repeated
view that children must be born to acquire their contingent property rights.
112. See notes 82-87 supra and accompanying text.
113. See, e.g., Scott v. McPheeters, 33 Cal. App.2d 629, 92 P. 2d 578, reh. denied
33 Cal. App.2d 629, 93 P. 2d 562 (1939) (statutory construction); Hornbuckle
V. Plantation Pipe Co., 212 Ga. 504, 93 S.E.2d 727 (1956) (fetus six weeks
old at time of injury); Daley v. Meier, 33 111. App.2d 218, 178 N.E.2d 691
(1961); Cooper v. Blanck, 39 So. 2d 352 (La. App. 1923) (statutory
construction); Torigian v. Watertown News Co., 352 Mass. 446, 225 N.E.
2d 926 (1957) (3-1/2 month fetus injured and born at 5-3/4 months can
recover although it died 2-1/2 hours after birth) ; Womack v. Buckhorn,
187 N.W.2d 218 (Mich. 1971) (injury to fetus at four months); Bennett v.
Hymers, 101 N.H. 483, 147 A. 2d 108 (1958); Smith v. Brennan, 31 N.J. 353
157 A. 2d 497 (1960); Kelly v. Gregory, 282 App. Div. 542, 125 N.Y.S.2d
696 (1953), app. granted, 283 App. Div. 914, 129 N.Y.S.2d 194 (1954)
(fetus 3 months at time of injury); Sinkler v. Kneale, 401 Pa. 267, 164
A. 2d 93 (1960); Sylvia v. Gobeille, 220 A. 2d 222 (R.I. 1966); Yandell v.
Delgado, 471 S.W.2d 569 (Texas 1971). There are dicta in other juris-
dictions, see Panagopoulos v. Martin, 295 F.Supp. 220 (D.W. Va. 1969);
West V. McCoy, 233 S.C. 369, 105 S.E.2d 88 (1958), that a fetus must
have been viable when injured to recover after birth, but these are only
dicta, and some of the jurisdictions now permitting recovery formerly
said that such an action did not lie, until presented with a case, e.g.,
Poliquin v. MacDonald, 101 N.H. 104, 135 A. 2d 249 (1957); Leal v. C.C.
Pitts Sand & Gravel, Inc., 419 S.W.2d 820 (Tex. 1971), overriden respec-
tively by Bennett and Yandell, supra.
114. See, e.g., Bennett, "The Liability of Manufacturers of Thalidomide to the
Affected Children," Austral. L.J. 39:256,263, 1965.
115. But see Porter v. Lassiter, 91 Ga. App. 712, 87 S.E.2d 100 (1955) (draws
no distinction between viable and quick fetuses under wrongful death
statute) .
116. See, e.g.. Mace v. Jung, 210 F.Supp. 706 (D. Alas. 1962).
13-46
REFERENCES (Continued)
The mother may have a cause of action for her mxscarriage, however. Cf.
Graf V. Taggert, 43 N.J. 303, 204 A. 2d 140 (1964). Some courts have
also said, as regards stillborn viable fetuses as well, that there is
no way to prove the pecuniary loss to the beneficiaries under the wrongful
death statutes.
See, e.g., Utah Copper Co. v. Industrial Commission, 57 Utah 118, 193 P. 24
(1920); Morrow v. Scott, 7 Ga. 537 (1849) (dictum, quoting Blackstone) .
The protection afforded to the unborn child does not rest on any theory
that he is already a person, however, since a trust which provides for
possible unborn beneficiaries may not be set aside without their represen-
tation before the court, including representation for those not yet con-
ceived, who are certainly not "persons." See, e.g.. Hatch v. Riggs Nat.
Bank, 361 F.2d 559 (D.C. Cir. 1966); Gunnell v. Palmer, 18 N.E.2d 202,
370 111. 206 (1938); McPherson v. First & Citizens Nat. Bk. of Elizabeth
City, 81 S.E.2d 386, 240 N.C. 1 (1954) (reformation refused on grounds
that guardian ad litem could not adequately represent the interests of the
children not yet in existence); Caine v. Griffin, 103 S.E.2d 37, 232, S.C.
562 (1958) .
Kyne v. Kyne , 38 Cal . App.2d 122, 100 P. 2d 806 (1940); Metzger v. People,
98 Colo. 133, 53 P. 2d 1189 (1936). Yet in Burns v. Alcala, 43 U.S.L.W.
4374 (1975), the Supreme Court held that Congress, in using the term
"dependent child" in the Social Security Act, 42 U.S.C. §506(a), intended
the ordinary meaning of a child already born, so that states which deny
pregnant women AFDC benefits for unborn children are not in violation of
federal requirements .
See, e.g., Raleigh-Fitkin-Paul Morgan Memorial Hosp. v. Anderson, 42 N.J.
421, 201 A. 2d 537, cert, denied, 377 U.S. 985 (1964) Cf. In re Matter
of Bentley, 102 Wash. L. Rptr. 1221 (D.C. Super 1974) (declining to order
transfusion for pregnant woman where it was not necessary for safe delivery
of child, although a two percent chance existed that it would be needed to
keep the mother alive); Hoener v. Bertinato, 67 N.J. Sup. 517, 171 A. 2d
140 (1961) (order granted for blood transfusion of child, over parents'
religious objections, to be carried out immediately after the child was
born). A guardian cannot have a legal abortion enjoined, however, on the
grounds of protecting a person. McGarvey v. Magee-Womens Hospital, 340
F.Supp. 751 (W.D. Pa. 1972); Byrn v. New York City Health and Hospitals
Corp., 329 N.Y.S.2d 722 (1972).
See note 96 supra and accompanying text.
See, e.g., Hodgson v. Anderson, 378 F.Supp. 1008 (D. Minn. 1974), appeal
dismissed and remanded sub nom. Spannaus v. Hodgson, 43 U.S.L.W. 3415
(Jan. 27, 1975); Planned Parenthood of S.E. Penna. v. Fitzpatrick, No.
74-1220 (E.D. Pa. Oct. 10, 1974).
Mass. 1974 Reg. Sess. Laws, ch. 421 (1974).
13-47
REFERENCES (Continued)
124. The Massachusetts law also requires that the experiment "not substantially
jeopardize the life or health of the fetus," but this limitation is
probably unconstitutional and is, in any case, not necessary if the
hypothesis in the test is correct.
125. Capron, "Informed Consent in Catastrophic Disease Research and Treatment,"
University of Pennsylvania Law Review 123:340, 1974.
13-48
14
A REPORT ON LEGAL ISSUES
INVOLVED IN RESEARCH ON THE FETUS
John P. Wilson, LL.B.
JOHN P. WILSON, LL.B.
Mr. Wilson is presently Associate Dean and Director
of the Legal Studies Institute of Boston University.
PD 304180-5
A Report on Legal Issues
Involved in Research on the Fetus
INTRODUCTION
The subject of fetal experimentation, until now largely unheeded by the
general public, is likely to become a new topic of national controversy. It is
linked inextricably with abortion, and like abortion it poses a complex clash
of values and public policy considerations.
The outlines of the dilemma are easy to discern — perhaps the most easy in
a city such as Boston which is host to over eighty hospitals in its forty-three
square miles.' In Boston are some of the most presitigious hospitals in the
world. Much of the research which takes place in them is dependent on fetal
tissue, 2 and the Massachusetts medical community has strongly supported such
research in the interest of eliminating many of the ills which afflict mankind.
Arrayed against the doctor-researchers is a strong "pro-life" movement which,
believing that hiiman life commences at conception but having suffered a defeat
on abortion, is determined to limit the implications of this defeat.
And one should not underestimate the fury of the conflict. Nearly
900,000 abortions were performed in the United States last year, an increase of
30 percent in two years; in New England there were 51,700 legal abortions last
year, compared to 6,200 in 1972.^ The products of these abortions are a rich
source for research. The doctors are seen by some as callous, impersonal
investigators who place scientific inquiry over "human" suffering. Those who
believe a fetus is a child draw on more than conservative doctrine or religious
belief to sustain their position. They can point out that in the nineteenth
century, a not-so- long-ago but less sensitive time, children from orphanages
and foundlings were used for research.^ Our sense of protection is a relatively
recent phenomenon and must be zealously nurtured. Even now hundreds of children
are killed every year by their parents or parent surrogates, the very ones who
should be most concerned with their welfare.^ And potential children are put at
risk, e.g., women intending to have abortions have agreed to be injected first
with rubella vaccine to determine whether the vaccine would harm the fetus. ^
The research community disputes the assertion that a fetus is human, or at
least protectible in the fully human sense, and its spokesmen point to the sub-
stantial benefits which have resulted from fetal research. Across the country
doctors and researchers studying the diseases of very young children, both
before and after birth, contend that prohibitions on their work will needlessly
condemn countless future babies to illness and death. ^ In fact fetal research
has resulted in saving babies from abortion; recently the use of a new technique
for examining the fetus in utero and removing a sample of its blood from the
14-1
placenta convinced five women with sickle cell trait or Cooley's anemia trait
not to have abortions.^ In a letter to the New England Journal of Medicine,
John F. Enders of Children's Hospital Medical Center in Boston said:
"Most physicians and biomedical scientists will agree, I believe,
that the legal prohibition of the investigative use of embryonic
and fetal tissues derived from dead h\jman embryos or fetuses will
gravely retard the advancement of medical knowledge in many areas.
Examples of such areas are: (1) the further understanding of the
causes and development of means for the prevention of fetal abnor-
malities; (2) the alterations in cellular mechanisms underlying
transformation of normal human cells to cancer cells and the
immunologic factors involved in resistance to cancer; and (3) the
development of vaccines not now available against viral and other
infectious micro-organisms such as varicella virus, cytomegalo-
virus and the agents of hepatitis and mycoplasma. Regarding the
last mentioned area of investigation, it should be realized that
the development of the prophylactics now generally employed in
the prevention of poliomyelitis, measles and German measles stemmed
from the results of original studies with human embryonic tissues."^
II. ABORTION
In terms of legal and factual analysis, fetal experimentation cannot be
fully understood without a corollary understanding of abortion and the law
relating to it. Both topics are fueled by emotional energy from the same source.
As the facts and law are reasonably well known, however, the information pre-
sented here will be limited.
1. Abortion Procedures
During the first 12 weeks, or first trimester, of pregnancy, dilation and
curettage (a "D and C") or suction curettage are employed. 1° The former involves
widening the mouth of the cervix and scraping and emptying the uterus manually.
The latter involves the use of a vacuum-powered device to scrape the fetus, pla-
centa and amniotic sac from the uterine wall, homogenize them and suck them out
of the uterus. '^
Abortions are generally not performed after 12 weeks until the sixteenth
week of pregnancy,'^ but between 16 and 20 weeks two methods are used: injec-
tion of a saline solution into the uterus or intravenous injection of the drug
prostaglandin. In almost all cases a saline solution kills the fetus, ^^ often
deforming it hideously-'* and burning the first layer of flesh from its body.^*
Prostaglandin may not kill the fetus,-'* but at least 90 percent of the fetuses
aborted by this method are delivered dead.'^ If they show some signs of life —
a determination made by the delivering physician — they generally "die" within
minutes or at most a few hours. ^^
14-2
If other methods do not produce an abortion, a hysterotomy, or little
Ceasarian, is performed. This is a surgical procedure in which the fetus is
removed intact from the uterus, and it may be the procedure of choice for preg-
nancies between 20 and 24 weeks.-" This method poses the least risk to the
fetus and the greatest risk to the mother. ^°
Maternal deaths from complications arising from suction curettage are
0.4 per 100,000 cases; from saline infusion, 16.3 per 100,000 cases; from hys-
erotomy, 222.8 per 100,000 cases. The overall maternal mortality rate, includ-
ing deaths from abortion and from childbirth at full term, is 25 per 100,000
cases. ^^
At the Boston Hospital for Women, fetal remains are regarded as patho-
logical specimens for any abortion when the gestational term is under 20 weeks.
According to hospital policy, if the gestational term is over 20 weeks a birth
or stillborn certificate is filled out. A death certificate is required by law
for any fetus over 20 weeks gestation if born dead.^^ In the past two years,
the hospital has performed only two or three abortions in the last trimester of
pregnancy. A premature infant weighing approximately 1 pound 13 ounces was
delivered at 28 weeks of pregnancy and was kept alive through heroic effort.
After two and one-half months, the baby, then weighing 6 pounds 15 ounces, was
sent home. The cost of hospitalization and medical treatment was $30,000.^^
2. Roe V. Wade ^'*
Although Roe v. Wade was a decision about abortion, its holding and dicta
have direct relevance to fetal experimentation. In this latter regard, it is
important to state precisely what the opinion said and did not say. I start with
the Court's own summary of its now well known trimester scheme:
(a) For the stage prior to approximately the end of the first tri-
mester, the abortion decision and its effectuation must be left
to the medical judgment of the pregnant woman's attending physi-
cian.
(b) For the stage subsequent to approximately the end of the first
trimester, the State, in promoting its interest in the health of
the mother, may, if it chooses, regulate the abortion procedure
in ways that are reasonably related to maternal health.
(c) For the stage subsequent to viability, the State in promoting its
interest in the potentiality of human life may, if it chooses,
regulate, and even proscribe, abortion, except where it is neces-
sary, in appropriate medical judgment, for the preservation of the
life or health of the mother. ^s
In arriving at this formulation, the Court determined that a woman's right
of privacy is protected by the Fourteenth Amendment,^® that the decision to have
14-3
an abortion falls within this right, ^' and that the right to abortion is funda-
mental and can only be subject to regulation when there is a compelling state
interest. 26 The State has two legitimate interests — maternal health and the
protection of the potentiality of human life.^' Each acquires greater signifi-
cance throughout the duration of pregnancy; this maturing of significance per-
mits limited state regulation during the second trimester and provides the state
with a compelling interest in limiting abortion, if it chooses, during the third
trimester.^"
In terms of fetal rights, what did Roe decide? The Court held that
"the word 'person,' as used in the Fourteenth Amendment, does not include the
unborn. "31 a fetus in utero therefore enjoys no Fourteenth Amendment rights
and, in all probability, since the Courts' constitutional analysis was not
limited to the Fourteenth Amendment, ^^ no other constitutional rights until
after birth. A state may choose not to restrict abortions at any time during
pregnancy, and a fetus has no constitutional right to object, despite the harm
that might occur. On the other hand, a state's "important and legitimate inter-
est in protecting the potentiality of human life"33 becomes "compelling" at
viability, or during the third trimester. "If the State is interested in pro-
tecting fetal life after viability, it may go so far as to proscribe abortion
during that period except when it is necessary to preserve the life or health
of the mother. "3* The Court described "viable" as the point at which the fetus
is "potentially able to live outside the mother's womb, albeit with artificial
aid. " 35 It went on to say that " [v] lability is usually placed at about seven
months (28 weeks) but may occur earlier, even at 24 weeks." 36
What of an abortus or premature infant outside the womb? Roe v. Wade dealt
(perhaps badly, as I shall point out in the next section) with a woman's rights
vis-a-vis the unborn being within her. The word "person," said the Court, does
not include the unborn. 3' What of those who are "born"? At one point the major-
ity opinion rather offhandedly remarks that the law has been reluctant to endorse
any theory that life begins before live birth. 3^ a "live birth" is not explained,
and at another point the Court states "We need not resolve the difficult question
of when life begins. When those trained in the respective disciplines of medi-
cine, philosophy and theology are unable to arrive at any consensus, the judi-
ciary, at this point in the development of man's knowledge, is not in a position
to speculate as to the answer. " 39
Roe V. Wade leaves many questions unanswered. It does not define "birth"*"
(partial or total emergence?*^ severance of the umbilical? ^^ ) , "viable" (no
precise gestational age; a medical judgment?) , "artificial aid" for sustaining
premature but "viable" infants (equipment available at the most advanced, aver-
age, or least advanced hospital? equipment available at the site of the abor-
tion?) , the point at which "life begins," and, perhaps most importantly, the
extent of legitimate state interests in protecting previable fetuses and the
previable "born."
3. The Massachusetts Cases
Because Roe v. Wade left unanswered questions, because Boston has a sub-
stantial antiabortionist population, because it was an election year, and because
fetal experimentation is linked to abortion, it is hardly surprising that the
issues of experimentation and abortion have surfaced in two criminal cases in
Massachusetts which have captured national attention. It all began with a brief
article in the New England Journal of Medicine authored by three doctors at the
Boston City Hospital . ^^ Briefly summarized, their article described tests to
determine which of two drugs reached a fetus in sufficient concentrations to
prevent congenital syphilis where the mothers were allergic to penicillin.
Thirty- three women, all of whom had requested abortions and had given written
consent to the experiment, participated in the study. Following the abortions,
fetal tissues were obtained, and an assay for antibiotic content was performed.
A valuable finding, that the drug clindamycin passed the placental barrier more
readily, was obtained.
Following a hearing by the Boston City Council, the Suffolk County District
Attorney's Office began an eight-month investigation culminating in the issuance
of indictments in April 1974, against the three doctors who wrote the article
and against a pathologist who assisted them.^* The indictments charged each with
"wilful and unauthorized removal of body for purpose of dissection" and "know-
ingly aiding in the wilful and unauthorized removal of body for purpose of dis-
section" in violation of M.G.L.A. Ch. 272 §71. The statute speaks in terms of
"a human body," and the indictments allege that the dissections were performed
on fetuses more than twenty weeks old.''^ Trial of the doctors is tentatively
scheduled for June 1975."^
In the process of the investigation of the research doctors, a representa-
tive of the Suffolk County District Attorney's Office found two dead fetuses at
the Suffolk County Mortuary. One was allegedly 24 weeks old, and a certificate
listing cause of death for it could not be found. Kenneth Edelin, the doctor
who performed the abortion (a hysterotomy following several unsuccessful attempts
to use saline solution) , was charged in an indictment with assaulting and beat-
ing "a certain person, to wit, a male child . . . and by such assault and beat-
ing did kill said person." ''■'
At the trial the age of the fetus was disputed by several witnesses. The
prosecution maintained that it was between 24 and 28 weeks in gestation and
viable.^* Although the prosecution also contended that the "child" was born when
Dr. Edelin detached the placenta from the uterine wall and that Dr. Edelin suf-
focated the fetus in the uterus after detachment, the judge charged the jury that
a fetus is not a person, that birth is defined as "the process which causes the
emergence of a new individual from the body of its mother," and that a person is
one who is born, that is, outside the body of the mother. *9 The only eyewitness
for the state testified that the fetus showed no sign of life when it was removed
from the mother . ^°
The jury convicted Dr. Edelin of manslaughter. In an interview, several
of the jurors said their guilty finding was based on the belief that Dr. Edelin
was negligent in not attempting to save the life of a premature infant while per-
forming an abortion.^' A picture of the "premature infant" had a powerful effect
in moving the jury toward conviction. ^^ According to Dr. Mary Ellen Avery, chief
physician at Children's Hospital Medical Center in Boston: "This judgment could
lead to extraordinary efforts to sustain life against all odds of a successful
outcome of an intact human being. "^^
14-5
III. SHOULD THERE BE FETAL EXPERIMENTATION? VmAT KIND? IN UTERO OR EX UTERO?
PREVIABLE OR VIABLE? WHO DECIDES?
A few terms must be clarified at the outset. It seems sensible to adopt
the definitions in the Proposed Rules of the Department of Health, Education,
and Welfare pertaining to the Protection of Human Subjects.^"
". . . (b) "Biomedical research, development, and related activities"
means research, development, or related activities involving biological
study (including but not limited to medical or surgical procedures,
withdrawal or removal of body tissue or fluid, administration of chemi-
cal substances or input of energy, deviation from normal diet or hygiene,
and manipulation or observation of bodily processes) .
(c) "Pregnancy" encompasses the period of time from confirma-
tion of implantation to the time of delivery.
(d) "Fetus" means the product of conception from the time of
implantation to the time of delivery.
(e) "Viability of the fetus" means the ability of the fetus,
after either spontaneous or induced delivery, to survive (given the
benefit of available medical therapy) to the point of independently
maintaining heartbeat and respiration. If the fetus has this ability,
it is viable and therefore a premature infant.
(f) "Abortus" means a fetus when it is expelled whole, prior
to viability, whether spontaneously or as a result of medical or
surgical intervention. The term does not apply to the placenta;
fetal material which is macerated at the time of expulsion; or cells,
tissue or organs excised from a dead fetus . . . . " ss
These definitions, of course, are no doubt the result of a complex bal-
ancing process. The period from conception to implantation is not explained.
It is clearly tautological to define research as research, although the diffi-
culties of definition here may require a connotative rather than denotative
approach. Cells, tissue or organs excised from a dead fetus are not to be
defined as an abortus, and cells, tissue or organs excised from an abortus are
not defined at all.
As the definition is not clear, it should be pointed out that the objec-
tives of research may vary substantially. An article in the Stanford Law
Review^^ (with reference to human subjects) states:
"The objectives of experiments on human beings cover a wide spectrum,
but may be classified roughly as therapeutic or nontherapeutic. Many
experiments are intended to benefit the subject (therapeutic experi-
mentation) . Frequently a doctor must treat a patient with an untried
method because no "accepted" treatment exists. A doctor may also use
a new method of treatment where other procedures are regarded as
"standard practice," thinking that the new method will prove more
14-6
beneficial to his patient or be equally beneficial to his patient
but lead to improved treatment for other sufferers of similar dis-
orders. On the other hand, many experiments are not intended to
benefit the subject (nontherapeutic experimentation) , but are con-
ducted solely in the pursuit of new knowledge. The subject might
be a patient under a doctor's care for an unrelated ailment ...
or he might be a healthy volunteer. Different standards should
govern therapeutic and nontherapeutic experimentation. The thera-
peutic purpose itself serves to justify a doctor's exposing a ter-
minal leukemia patient to substantial risk in an effort to prevent
or postpone imminent death, while a stronger independent justifi-
cation should be required for allowing a researcher to expose a
healthy volunteer to a similar risk simply to gain new knowledge."®^
From the above definitions it should be apparent that in considering fetal
rights in research, it is important to distinguish between different types of
research, different stages of gestation, different states of being (in utero or
ex utero) , and the different, countervailing interests present in each situation.
In launching this consideration, I return first to Roe v. Wade. The wis-
dom of the Court's opinion has been seriously criticized as an unjustifiable
extension of the constitutionally protected right to privacy and as court-made
legislation. 5^ Professor John Ely of Harvard Law School says: "... What is
frightening about Roe is that this superprotected right [a woman's freedom to
choose an abortion] is not inferable from the language of the Constitution, the
framers' thinking respecting the specific problem in issue, any general rules
derivable from the provisions they included, or the nation's governmental
structure . . . . " ^^ He argues that the opinion is an unwarranted exercise of
substantive due process, a twin to Lochner v. New York^° but possible more per-
nicious because it employs a higher standard of judicial review. °-'
The results in Roe, but not its legal reasoning, has been defended by
another Harvard Law School professor, Lawrence Tribe. ^^ Professor Tribe argues
that the question "when life begins" has become an essentially religious issue, ^'^
not resolvable by resort to the slippery slope of biological development,®* and
that if governmental decisions are based on the pervasive interference of reli-
gious groups in legislative considerations, the establishment clause must be
invoked unless there are compelling, wholly secular reasons for the legislation.®^
As in Roe, in his view the government may intervene only after viability, because
only at that point in time is the fetus in the same status as an infant for the
secular purpose of protecting it from infanticide.®®
I agree with Professor Ely that a state may claim a compelling interest
in protecting human life, and this interest could override the mother's consti-
tutional right to privacy at any point in time during pregnancy. Moreover, the
interest in protecting potential life should be as important a secular purpose
as the state's interest in enacting Sunday closing laws. The Supreme Court has
upheld such laws®^ for the less than compelling secular purpose of promoting
the recreational pursuits of the general population despite the obvious sectar-
ian influence that fostered these laws.
14-7
These objections notwithstanding, Roe v. Wade is the law. And the decision
makes some pragmatic sense, as even Professor Ely admits. It is my argument,
however, that the opinion should be construed narrowly, particularly because it
is questionable in terms of constitutional doctrine. It is a decision about the
rights of the mother vis-a-vis the fetus in the context of abortion. Because the
fetus may be killed in abortion, it does not necessarily follow that it has no
rights in other contexts where the mother's right to privacy is nonexistant or
less compelling. The right to abort does not infer a right to experiment any
more than a state's right to execute a felon confers a right to inflict cruel
and unusual punishment.
It is unlikely, however, that the Court would be so inconsistent as to
define the fetus as a person in terms of the Fourteenth Amendment for one pur-
pose and as a nonperson for another purpose. It has spoken in Roe that the fetus
is not a person;^' the Court has the power to define the terms of the Constitu-
tion, ^° and this interpretation should be taken as definitive. Several questions,
therefore, must be answered.
1. Does the fetus, even though not a person, possess rights infer-
rable from areas of the law unrelated to abortion sufficient to
enable the state or federal government to compel, prohibit, or
limit experimentation?
2. Is an abortus, or premature infant ex utero , a person? What
rights to compel, prohibit, or limit experimentation would either
have as a person?
3. May federal or state lawmaking bodies compel, prohibit, or limit
experimentation on an abortus, or premature infant ex utero, if
not a person?
In the context of experimentation, I assume that any being, if defined as
a person for purposes of the Fourteenth Amendment, is entitled to an array of
protections under that amendment which may prohibit a state from infringing on
its "life" or "liberty." In the absence of a definition of personhood, or in
the event that a being is declared not to be a person by the Supreme Court, state
legislative enactments or court decisions would be controlling in terms of
defining fetal rights, unless Congress preempted the field, although a person
protected by the Fourteenth Amendment- -the mother, perhaps — might assert a con-
stitutionally protected property interest in it. Regulations promulgated by the
Department of Health, Education, and Welfare would be controlling in the dispo-
sition of its funds in the absence of state law, but a researcher would be
required to conform to state law if it imposed higher standards than were imposed
by federal regulations.
1. The Rights of the Fetus in Areas of the Law Other Than Abortion
States have long exercised the right to grant a fetus--or the parents of
one — certain rights. This exercise has an honored, historical heritage, because
Judeo-Christian civilizations have long looked upon fetuses, in at least some
contexts, as human beings. "When men strive together, and hurt a woman with
14-8
child, so that there is a miscarriage . . . the one who hurt her shall be
fined . . . ." (Exodus XXI, 22, emphasis added). ''And Joseph also went from
Galilee . . . to . . . Bethlehem ... to register, together with Mary his
espoused wife, who was with child." (Luke 2, 1-5, emphasis added).
(a) Property Law. Anglo-American law has accorded the fetus legal
recognition and protection in several fields. The law of property, for example,
recognizes rights of the unborn child from the moment of conception. In the
1834 case, Hall v. Hancock, ^^ where the issue was whether a grandchild bom
almost nine months after the death of the testator was entitled to share with his
four brothers in the testator's bequest to such grandchildren "as may be living
at my death," the court held that a child en ventre sa mere^^ is within the des-
cription of "children living." Most states followed this Massachusetts opinion.^^
In other property situations, as well, "the law regards an infant en ventre as
in being. It may take a legacy; have a guardian; an estate may be limited to its
use, etc."^* However, the property rights of a child in utero are not perfected
until and unless the child is born alive. ^^
The liberal construction of fetal property interests apparently stems from
an attempt to carry out testator intent, the presumption being that the testator
would not wish to exclude any of his issue. Because the interest of the fetus
derives largely from testator intent, the competing interests of other siblings
are usually regarded as insufficient to divest the fetus of its rights.
(b) Homicide Law. "It is undisputed that at the common law, abortion
[including killing of the fetus] performed before 'quickening' — the first recog-
nizable movement of the fetus in utero, appearing usually between the tenth and
eighteenth weeks of pregnancy — was not an indictable offense. "'^ Some legal
scholars maintain that the common law refused to recognize any feticide as homi-
cide, demanding that a child be fully born (i.e., entirely separated from its
mother, with an entirely independent life with the umbilical cord cut and with
its own breathing and heart action) in order to be treated as the victim of
homicide.''^
This is disputed by others who believe that the early common law required
not birth, but only quickening, or animation, for a fetus to be protected by the
laws against homicide. ^^ Whatever the early English law, it is generally agreed
that by the mid-seventeenth century the common law had adopted the "born alive"
theory.^®
Most American jurisdictions have followed the "born alive" theory and
apply the law of homicide only in cases of infants born alive .^° Some state
courts, however, have held that a fetus shall be regarded as a human being for
the purpose of homicide statutes when it has reached viability. ^^ Several have
required only a showing of "quickening" in fetal manslaughter cases. '^ And a
number of others have pushed the definition of a human being for purposes of
manslaughter back to the ''moment"*^ of conception.*"
(c) Tort Law. Early American tort law, as exemplified by the language
of a Massachusetts opinion, Dietrich v. Northampton,^^ denied recovery for fetal
injury on the ground that "the unborn child was a part of the mother at the time
of the injury . . . . " The Dietrich decision was followed universally for a
number of years, but its basic premise was challenged in 1900 by J. Boggs, dis-
senting in Allaire v. St. Luke's Hospital^^ who argued that a fetus must be
regarded as constituting a life distinct from that of its mother v/hen it reaches
the prenatal stage of viability.
"The logic of Justice Boggs met with increasing approval in subsequent
decisions, and a few jurisdictions began to recognize the surviving infant's
right of action for prenatal injuries."** "Beginning with a decision in the
District of Columbia in 1946, a series of more than thirty cases, many of them
expressly overruling prior holdings, have brought about the most spectacular
abrupt reversal of a well settled rule in the whole history of the law of torts."*'
Today there are few, if any, American jurisdictions in which recovery is not per-
mitted for wrongful fetal injury.'"
Of significance when considering fetal experimentation, "[m]ost of the
cases allowing recovery have involved a foetus which was then viable ....
Many of them have said, by way of dictum, that recovery must be limited to such
cases, and two or three have said that the child, if not viable, must at least
be quick. But when actually faced with the issue for decision, there are [approxi-
mately thirteen] jurisdictions which . . . have allowed recovery even though the
injury occurred during the early weeks of pregnancy, when the child was neither
viable nor quick."'-'
However, to maintain a suit upholding fetal rights in tort law, courts tra-
ditionally have required that the fetus be born alive. '^ Thus the potential for
human life is not sufficient to permit recovery in tort unless that potential is
actualized by at least momentary life after birth. In jurisdictions where this
rule survives, if a fetus is to be aborted, with no possibility of live birth,
so that any property or tort rights which it theoretically possesses have no pos-
sibility of ever being exercised, it is at least arguable that the fetus posses-
ses no such rights in the first instance. The rule requiring live birth has,
however, been undergoing rather rapid change in wrongful death actions during the
past 20 years. As of last fall, between 22 and 24 jurisdictions would permit an
action for the wrongful death of a stillborn fetus who was fatally injured while
viable; 12 jurisdictions would not.'^ One state, Georgia, permits such an action
for children injured when not yet viable but only "quick. "5"
(d) Welfare Law. Another context in which the law recognizes fetuses
as possessing some degree of "personhood" is that of welfare benefits. The
meaning of "dependent child" in the Federal Aid to Families with Dependent Chil-
dren (AFDC) program'^ has caused much confusion in the courts.'^ Nowhere in the
statutory definition is there mention of the unborn. "The statute simply refers
to needy children who are deprived of the care and support of a parent and who
are 'under the age of eighteen. 's^ HEW regulations refer to the unborn as a
group for which federal matching funds are available, '* but the regulations are
not phrased in mandatory terms. Accordingly, HEW has approved both state plans
which exclude the unborn from coverage and plans which do not. At present, only
19 states include the unborn in the category of eligible dependent children.""
Because there was no Congressional intent explicitly to exclude the unborn
from these benefits, °° and because "in terms of need and dependency, many unborn
14-10
children are in far more severe circumstances than born children . . . " '°i five
of the six federal appeals courts which have considered the matter during the
past two years have ruled in favor of fetal eligibility . i°2 one of these cases
is currently before the U.S. Supreme Court. i°' Its decision should clarify the
status of fetuses for AFDC benefits and perhaps for other areas as well.
From the above, it can easily be seen that the extent of fetal rights is
very much a function of the particular context in which they are asserted. These
rights may even supersede the constitutional rights of the mother. In a pre-i?oe
New Jersey case-""* a mother, on religious grounds, had refused blood transfusions
necessary to save her unborn child's life. The Court's opinion stated: "We are
satisfied that the unborn child is entitled to the laws' protection and that an
appropriate order should be made to ensure blood transfusions to the mother in
the event that they are necessary in the opinion of the physician in charge at
the time." i°5
2 . In Utero — The Viable Fetus
For fetal research, especially since the Roe decision, the clearest demar-
cation line (from a legal but not biological viewpoint) must be that of viability.
It is at viability, the Roe court said, that a state's interest in protecting
"the potentiality of human life" becomes so compelling that the state may pro-
tect that interest even over the constitutional right of the woman to abort. ^°^
It would appear that if a state may act to protect fetal interests over the very
strong interest of the woman wishing to abort, it may surely protect fetal inter-
ests over less compelling interests such as nontherapeutic research which is con-
ducted on the mother or fetus for the benefit of medical science or society at
large. In so doing, it may ban all nontherapeutic research or limit such research
to procedures involving minimal risk or study and diagnosis .^°^
When therapeutic (including diagnostic) research is involved, however, two
questions arise. May a state proscribe therapeutic research on the mother when
there may be potential harm to the fetus? May the state compel therapeutic
research on the fetus when there may be potential harm to the mother?
In my view, before a mother undertakes therapeutic research, there should
be a careful weighing of potential risk of harm to the fetus and the potential
benefit to the mother. If the mother's need is not serious, the research should
be delayed until after she gives birth, first considering any additional risk to
the mother such a delay would entail.
If her situation is relatively serious, however, and if an abortion would
not pose as great a risk to the mother and fetus as the risks of research, then
every effort should be made to convince her to abort. We know, however, that a
hysterotomy would be performed at this stage of pregnancy, and it is the most
dangerous abortion procedure to the mother. Consequently, if the risks in abor-
tion are great, or if she simply refuses an abortion (in all probability she can-
not be compelled to have one ^°* ) , then the same weighing of the interest of
mother and fetus should be performed before research is permitted.
If the situation is life-threatening to the mother or is potentially very
deleterious to her health, I would weight the balance conclusively in her favor,
regardless of the risk to the fetus. She is the life-in-being, quite possibly
with a husband and other children. Roe does not permit a state to proscribe the
abortion of a viable fetus "when it is necessary to preserve the life or health
of the mother. "^°' While a right of privacy covering therapeutic experimentation
is no more apparent than was such a right covering abortion in Roe, the public
policy justification of preserving maternal life or health is sound in both
contexts. Roe does not define health,'^° but I would limit it in the research
context to the possibility of grave impairment of the mother's physical or psy-
chological well-being.
A somewhat similar weighing of interests should apply with respect to
therapeutic research solely for the benefit of the fetus. If the research can
be delayed until after birth, it should be. If it is necessary but poses a risk
to the mother's health, she should be urged to obtain an abortion first, if pos-
sible, so that the experimentation on the fetus will be outside her womb. How-
ever, if she objects to an abortion but consents to the research, her consent
must be honored if she is an adult and legally competent. If the mother is an
adolescent or not otherwise competent, the risks and benefits to each party must
be weighed, but the mother's interest should take precedence as she is the life-
in-being.
Because judgments in this area will be based on a complex set of variables,
statutes or regulations can probably do little more than proscribe "unnecessary"
research, list guidelines incorporating the considerations discussed above, and
leave the decision in specific cases to the women and her physician with, per-
haps, the concurrence of another consulting physician or of a medical research
board. A major difficulty for these parties may occur in determining whether
research provides a "benefit." If research may sustain the life of a fetus
regardless of a possibly impaired condition and the impossibility of it ever
enjoying a "full" human life, some would argue that such research is not benefi-
cial. But the law generally endorses efforts to sustain life, however impaired
that life may be.''' Thus some recent state statutes which attempt to ban all
research on live fetuses "^ probably go further than their authors intended by
presumably including within their proscription even research for the benefit of
the fetus.
3. In Utero — The Previable Fetus
Living, previable fetuses, like viable fetuses, enjoy no constitutional
rights. Some older judicial opinions, e.g., Dietrich v. Wortha/npton, "^ go far-
ther than Roe v. Wade and hold that fetuses are merely part of the woman bearing
them and thus have no independent rights whatsoever. Under this theory the woman
enjoys unrestricted authority over the fetus.
But, unlike the woman's appendix, the fetus (as well as the placenta, amni-
otic sac, and umbilical cord) is composed of chromosomes from her male partner
as well as herself. It therefore has a separate biological identity. The Roe
V. Wade decision did not, by its terms, give the woman absolute control over the
fetus. The Court held that the mother had a constitutional right to abort it.
that is, to remove it from her body. Death may be the natural and usual conse-
quence of abortion, but the Court did not explicitly grant the mother a right to
terminate fetal existence, nor did the Court grant her any right to experiment
with the fetus and possibly harm its future development.
It is therefore my opinion that there should be no difference in the rights
accorded to a previable or viable fetus. If the mother intends to carry a fetus
to full term, it should be protected against all but the most innocuous forms of
nontherapeutic research, whatever its stage of development. If therapeutic
research is required for either the mother or previable fetus, the same weighing
of interests should occur as in the case of the viable fetus. The mother's
interest should prevail conclusively only when there would be substantial danger
to her life or health. - -
What of the situation, however, where the woman has decided to have an
abortion? The fetus will die anyway. Indeed, it may suffer a violent death.
These fetuses, no longer possessing the potential to develop into full human
beings, represent a class for which a "potential life" rationale may be inappli-
cable.
Nevertheless, I do not favor research in this situation either, at least
until the moment of the abortion procedure. In the first place, a potential life
remains a potentially full and useful life until death. Its interests should be
protected as much as--and perhaps more than — those of a dying, adult person.
Another basis for my opinion is that the mother may change her mind. And the
mother has a right to freedom of choice in this area, in the form of her volun-
tary consent to a surgical or medical procedure. Her power to revoke her consent
to an abortion procedure would be compromised if the fetus were subjected to
experimentation in utero with the possibility of harm to it, thereby reducing her
desire to carry it to full term, i^''
A similar withdrawal-of-consent problem exists in adoptions of newborn
children. Frequently a mother who, before giving birth, has consented to sur-
rendering her child for adoption, wishes to withdraw that consent upon or shortly
after birth. To cope with this problem, "[a] number of states have statutes
which declare invalid any consent executed by a mother before the birth of the
child . . . [T]he British Adoption Act of 1958 . . . absolutely voids any consent
unless the infant is at least six weeks old on the date of the execution of the
document. " us
An equally difficult case involves the possibility of research on the fetus
during the abortion procedure. Here, if previable, the possibility of it being
"saved" to develop into a full human being no longer exists, and the mother can
no longer withdraw her consent. Some might contend that birth is a process,
whether spontaneous or induced, and the fetus, if intact, is "born" and a person
immediately following separation from the uterus. The jury in the Edelin trial
apparently adopted this position, although the charge to the jury differed, and
no case has so held. However, if complete separation from the mother is the stan-
dard, I would permit nontherapeutic research during the abortion procedure (see
my discussion of reasons in the section on the abortus, infra).
Federal or state law could also proscribe nontherapeutic research, even
if the previable fetus is not a person for purposes of the Fourteenth Amendment.
If a state lawmaking body decided to protect the rights of the previable fetus,
either before or during abortion, it could do so on the grounds that research
on the fetus has a brutalizing effect on society as a whole. To arrive at this
conclusion, the lawmaking body could find that the fetus experiences pain and
that such pain is not outweighed by a more weighty societal interest. To pursue
this analysis, we should inquire whether the fetus, like any sentient creature,
does in fact suffer pain and whether research is permitted on nonhuman, i.e.,
animal, subjects regardless of pain.
No one knows whether a fetus feels pain.^^^ The ability to perceive pain
is apparently a function of the degree of development of the nervous system, and
previable fetuses may not have developed to the sentient point. Also, pain
causes living creatures to avoid or withdraw from contacts, environments, and
situations which may injure them; in the previable state the fetus has no need
of such a physiological warning function, and it may therefore not have one.
However, fetuses react to stimuli at a gestational age of only a few weeks.
This may be a reflex action not indicative of pain,ii7 but there is no clear
evidence proving the validity of this assumption, nor is it apparent that con-
clusive evidence can be obtained in the near future. As many capacities which
serve no functional purpose until after viability and birth are acquired and
develop during the previable stage, ^^ there is no reason to believe that the
ability to experience pain does not also begin to develop early in gestation.
In any event, it would not be necessary to demonstrate conclusively the
presence of pain in order to regulate research. Statutes governing wrongful
death actions typically require that in order for damages to be awarded for the
decedent's pain resulting from a fatal injury, the pain and suffering must be
"consciously" experienced. ^^^ The formidable obstacles in determining whether
a fetus' experiences conscious pain are apparent. But in the case of cruelty to
animals, where difficulties of defining and determining mental state also exist,
legislatures have not required any showing of "consciousness." They make an
assumption that an animal experiences pain as we know it.
Animals, like the fetus, enjoy no constitutional rights. ^^° A rational
basis for the statutes banning cruelty to animals in most, if not all, states ^^-^
can be found in the dehumanizing and brutalizing effect on society of needless
cruelty inflicted on helpless creatures . ^^^ However, the rights which states
assign to animals are generally quite limited in the area of research, barring
only "unnecessary" infliction of pain, but permitting the use of animals for "the
purpose of scientific investigation, experiment ... or for the testing of drugs
or medicines ." '^^ In the case of animals, any pain necessarily associated with
research is considered acceptable in the interest of a greater societal good.^^"
An institution performing such research is generally licensed by states only
after an investigation of its standards, facilities, and practices shows that it
is "a fit and proper agency to receive such license" -"^^ and that the issuance of
a license is "in the public interest ." '^^ Also, some states provide that such
institutions may be periodically inspected by interested organizations such as
the Society for the Prevention of Cruelty to Animals. ^^^
14-14
If the state restrictions described above are justified in the case of
animal research, it is clear that a state may impose even greater controls in
the case of human fetal research. In fact, in my opinion a state (and possibly
Congress) may go so far as to ban such research, even though this restraint
impinges on the constitutionally protected activity of another. ^^®
4. Ex Utero — The Premature Infant
Research on the premature infant who has been born presents the easiest
case. As its name implies, it is not a fetus at all. Roe v. Wade, by necessary
implication, accords the infant the rights of a person. ^^' If the viable fetus
has rights against nontherapeutic research, a fortiori so must the infant. In
the case of therapeutic research, while its interests may conflict with those of
the mother, the allocation of rights is much easier than when it resides within
her womb. Efforts should be devoted to insure its health and survival, even if
its needs conflict with a constitutional right of a parent. ^''° Any experimental
procedure should be for the child's direct benefit. i^i
5. Ex Utero — The Abortus
If research on the premature infant ex utero presents the easiest case, the
question of research on an abortus is in many ways the hardest. To be sure, the
critical problem evident with the fetus — that to "get at" it one must also "get
at" the mother — is missing. The abortus is "on its own." But it is also, at the
present state of technological knowledge, a being consigned to death, if it is
not dead already. There is no longer the potential for human life in any mean-
ingful sense.
Having been "born," however, if one may refer to a spontaneous or induced
abortion as birth, it may have rights as a person. The cases, including Roe v.
Wade, are, to put it charitably, highly ambiguous on this issue. The first matter
to consider, therefore, is whether the abortus possess qualities sufficient to
give it standing as a person.
The amicus curiae brief of Dr. Bart Heffernan, guardian ad litem for the
class of unborn children in the state of Illinois, to the Supreme Court in the
case of United States v. Vuitch,^^^ contains a summary of the development of the
fetus. It points out that " [h]uman life is a continuum — all of it, fetal, infant,
adolescent, mature or aged, is in the process of becoming ." i33 while the brief
refers to the fetus, not an abortus, it is useful in its description of the
stages of development during gestation. Excerpts are presented below:
"From conception the child is a complex dynamic rapidly growing
organism. By the end of the first month, the child completes the
period of relatively greatest size increase and the greatest phys-
ical change of a lifetime. The month old child is 10,000 times
larger than the fertilized egg and will increase its weight six
billion times by birth.
"By the end of the seventh week, we see a well proportioned small
scale baby. In its seventh week, it bears the familiar external
features and all the internal organs of the adult, even though it
is less than an inch long and weighs only l/30th of an ounce. The
body has become nicely rounded, padded with muscles and covered by
a thin skin. The arms are only as long as printed exclamations
marks, and have hands with fingers and thumbs. The slower growing
legs have recognizable knees, ankles and toes.
"The new body not only exists, it also functions. The brain in
configuration is already like the adult brain and sends out
impulses that coordinates [sic] the function of the other organs.
The brain waves have been noted at 43 days. The heart beats
sturdily. The stomach produces digestive juices. The liver
manufactures blood cells and the kidney begins to function by
extracting uric acid from the child's blood. The muscles of the
arms and body can already be set in motion."
"The primitive skeletal system has completely developed by the end
of six weeks. This marks the end of the child's embryonic (from
Greek, to swell or teem within) period. From this point, the child
will be called a fetus (Latin, young one or offspring) .
"In the third month, the child becomes very active. By the end of
the month he can kick his legs, turn his feet, curl and fan his
toes, make a fist, move his thumb, bend his wrist, turn his head,
squint, frown, open his mouth, press his lips tightly together. He
can swallow and drinks the amniotic fluid that surrounds him. Thumb
sucking is first noted at this age. The first respiratory motions
move fluid in and out of his lungs with inhaling and exhaling res-
piratory movements . "
". . .By the beginning of the ninth week, the baby moves sponta-
neously without being touched. Sometimes his whole body swings
back and forth for a few moments. By eight and a half weeks the
eyelids and the palms of the hands become sensitive to touch. If
the eyelid is stroked, the child squints. On stroking the palm,
the fingers close into a small fist.
"In the ninth and tenth weeks, the child's activity leaps ahead.
Now if the forehead is touched, he may turn his head away and pucker
up his brow and frown. He now has full use of his arras and can bend
the elbow and wrist independently. In the same week, the entire
body becomes sensitive to touch."
14-16
"Dr. Arnold Gesell states that: 'By the end of the first trimester
(12th week) the fetus is a sentient moving being. We need not pause
to speculate as to the nature of his psychic attirbutes but we may
assert that the organization of his psycho-somatic self is now well
under way. '
"Further refinements are noted in the third month. The fingernails
appear. The child's face becomes much prettier. His eyes, previ-
ously far apart, now move closer together. The eyelids close over
the eyes. Sexual differentiation is apparent in both internal and
external sex organs, and primitive eggs and sperm are formed. The
vocal cords are completed. In the absence of air they cannot pro-
duce sound: the child cannot cry aloud until birth, although he
is capable of crying long before."
"From the twelfth to the sixteenth week, the child grows very rapidly.
His weight increases six times, and he grows to eight to ten inches in
height. " - ,. ,
"In the fifth month, the baby gains two inches in height and ten
ounces in weight. By the end of the month he will be about one foot
tall and will weigh one pound. Fine baby hair begins to grow on his
eyebrows and on his head and a fringe of eyelashes appear. Most of
the skeleton hardens. The baby's muscles become much stronger, and
as the child becomes larger, his mother finally perceives his many
activities. "
"In the sixth month, the child develops a strong muscular grip with
his hands. He also starts to breathe regularly and can maintain res-
piratory response for twenty-four hours if born prematurely. He may
even have a slim chance of surviving in an incubator. The youngest
children known to survive were between twenty to twenty-five weeks
old. The concept of viability is not a static one . . . ." ■'■''*
Where is the point of discontinuity? Is it viability, a line which has
moved back in the spectrum of fetal development with technological advances,
which may differ from child to child and which may vary with race?'^^ Is it
"quickening"? Is it implantation? Conception? As Professor Tribe has said:
"... [T]he advance of embryology and medicine over the past cen-
tury and a half rendered untenable any notion that the fetus sud-
denly 'came to life' in a physiological sense at a definable point
during pregnancy. Once the embryo's growth had been traced in a
14-17
continuous line from a single unfertilized ovum through the unbroken
processes of fertilization, cell division, segmentation (in the case
of identical twins) , implantation of the blastocyst in the uterine
wall, and gradual fetal development to the point of birth, those who
believed in the sanctity of the fetus from the 'moment' of quickening,
or from some other 'moment,' were deprived of the ability to link
their belief to any distinct physical or biological event other than
perhaps 'conception,' which was itself later revealed as a complex
and continuous process."'^*
As a response to this dilemma. Professor Tribe has suggested that "the
question when human life truly begins asks not for a discovery of the point at
which the fetus possesses an agreed-upon set of characteristics which make it
human, but rather for a decision as to what characteristics should be regarded
as defining a human being. "^^^ The Supreme Court declined to make this decision.^^^
And Sissela Bok, in an article addressed to the problem of abortion, has sug-
gested that "[w]e must abandon ... a definition of humanity capable of showing
us who has a right to live."^^' Instead, she argues for an examination of the
reasons for protecting life, stating that we cannot "simply equate killing an
embryo with murder . . . For it is important that most of the reasons why we
protect lives are absent here. It does not matter that the group of cells cannot
feel the anguish of pain connected with death, that it is not conscious of the
interruption of its life, and that other humans do not mourn it or feel insecure
in their lives if it dies."^*°
I find this reasoning persuasive in the case of abortion, and applied
analogically, I find it persuasive also in the case of experimentation on an
abortus. It is probable that the product of an early abortion, most likely
homogenized or mangled in any event through a "D and C" or vacuum curretage,
does not feel pain; and I, at least, do not recoil at the thought that it be
the subject of experimentation. Conversely, a premature infant struggling for
life, or an abortus which is destined to live for only a few minutes, evokes a
much different response. The chances of extrauterine survival of a 700 gram,
24 weeks old fetus are "extraordinarily remote, "■'''■' and only one in 250 of such
infants will survive for any length of time.^"^ Nevertheless, a sizable number
of infants in the 600-800 gram range — or about 1-1/3 to 1-4/5 pounds — are capa-
ble of sustaining life for at least a few minutes,^''-' sometimes hours, ^^* and to
me it is as disturbing to subject these beings to nontherapeutic experimenta-
tion as it would be to experiment on a terminally ill patient or a prisoner
condemned to death. If I even suspect that the abortus might suffer pain, I am
concerned about the brutalizing effect nontherapeutic experimentation would
have on me .
Having said the above, I am caught in another dilemma. Instead of the
continuum between less human and more human, I am confronted by another contin-
uum of growing reasons for protecting an abortus the further along it is in the
process of development. And here it is equally difficult to draw a line.^''^ The
best, but not entirely satisfactory, way to resolve this problem is to attempt
to draw lines at points which allow a substantial margin for error. Thus I sug-
gest that nontherapeutic research for minimally justifiable reasons be permitted
on an abortus before brain-wave activity can be measured, or until about six to
14-18
eight weeks. After that point, until approximately 18 weeks, I recommend that
such research be permitted only after greater justification of its purposes--
such as the development of vaccines to combat serious diseases. Beyond 18 weeks,^"''
I suggest that only therapeutic research be permitted on a living abortus, as I
would then regard it as a person.
Needless to say, state legislatures have not adopted this approach. Most
legislation prohibits experimentation on "live" fetuses; "live" is usually asso-
ciated with heartbeat, and heartbeat can occur as early as the first month of
gestation. ^""^ The statutes, however, are very confusing (a brief analysis of
them is set forth in the Appendix) . They occasionally make no distinction
between an adult, a premature infant (where the potential for life is present) ,
and an abortus (where heartbeat, in most instances, is only a momentary flicker
before death) . In Louisiana and Maine, life is defined as "beating of the heart,
pulsation of the umbilical cord, or movement of voluntary muscles, whether or not
the umbilical cord has been cut or the placenta is attached. " ■'''^ Maine adds the
word "definite," as if it were significant, to further define movement of volun-
tary muscles.
In this confusing morass, perhaps the one truly essential point to bear in
mind is that for purposes of assigning legal rights, the real question is: Who
decides? At the moment, in the absence of federal legislation and a definitive
interpretation of the personhood of an abortus under the Fourteenth Amendment by
the Supreme Court, it appears that a state legislature or court may decide. If
a state lawmaking body determines that an abortus is not a person, it may permit
research, but it equally is not precluded from imposing restrictions. The pre-
vious analysis of laws regulating cruelty to animals is applicable here. I do\ibt
that any person could raise a constitutional objection to state action in these
circumstances .
If, on the other hand, a lawmaking body concludes that an abortus is a per-
son, then it stands in the same capacity as a premature infant. Nontherapeutic
research should not be performed on it unless, in the opinion of the attending
physician, it is dead. However, if the abortus is dead, one must still inquire
into the authority physicians have to perform research on dead human beings, or
on the tissue of dead human beings.
The first problem to be confronted is that there is no uniformly accepted
definition of death. Black's Law Dictionary defines death as "the cessation of
life; ceasing to exist; defined by physicians as a total stoppage of the circu-
lation of the blood, and a cessation of the animal and vital functions consequent
thereon, such as respiration, pulsation, etc."^^° This definition is not espe-
cially useful in this age of artificial respirators and hearts.
The Ad Hoc Committee of the Harvard Medical School to Examine the Defini-
tion of Brain Death has proposed a definition which would require a flat EEC for
24 hours or longer and the absence of spontaneous responses and certain reflexes.^^^
Such an elaborate definition and test is probably not warranted in the case of a
newly delivered fetus. (Incidentally, such tests are at present not possible for
fetuses in utero, and even if they could be performed, they would fail to indi-
cate the presence or absence of life during the first few weeks of pregnancy.)
14-19
The Uniform Anatomical Gift Act was adopted by the Commission on Uniform
State Laws in 1968 and has now been adopted, with minor variations, by all fifty
states. '^2 In the Massachusetts statute (which is believed to be typical of
such laws generally) determination of time of death is explicitly left to the
attending physician. ■'^^ Some safeguards in the transplantation context are pro-
vided by forbidding that physician from participating in the removal or transplan-
tation of any organ. '^^ A comment by the commissioners specifically notes that
"no attempt is made to define the uncertain point in time when life terminates. "^^
They suggest that "the real question is when have irreversible changes taken
place that preclude return to normal brain activity and self-sustaining bodily
functions. " ^^^ By its terms, this definition may be irrelevant to an abortus.
A New York statute provides that "[F]etal death is defined as death prior
to the complete expulsion or extraction from its mother of a product of concep-
tion; death is indicated by the fact that after such separation, the fetus does
not breathe or show any other evidence of life such as beating of the heart,
pulsation of the umbilical cord, or definite movement of the voluntary muscles. "^^
It is the death of a child, not a fetus, if death occurs after expulsion or
extraction from the mother. The New York statute further provides that when
an abortion is performed after the twentieth week of pregnancy, a physician
other than the physician performing the abortion must be present to provide
immediate care in case of live birth. ^^^ If live birth occurs, the child is
accorded immediate legal protection by the laws of New York.^^^ Idaho and Utah
have similar provisions requiring lifesaving efforts for a "viable" fetus. ^*°
If, by whatever definition established by a state, the death of an abortus
or a premature infant is established, two questions remain: Who may validly
consent to the use of the remains for research? Who may perform such research?
Generally, if a decedent has expressed no preference as to the disposition
of his remains, his closest surviving relative's wishes in this regard will be
honored. If the father is present, it would probably be wise to require his
consent as well as the consent of the mother. "As in the case of the mother, the
period of gestation is for the father one of anxiety, anticipation, and growth
in feeling for the unborn child . . . The modern trend is for fathers to take
a more active role in pregnancy and, indeed, to participate during the mother's
labor and delivery of the child. "'^^
Under the Massachusetts' Anatomical Gift Act, which is part of the chapter
on Promotion of Anatomical Science, unless the decedent has indicated otherwise,
a relative or guardian may donate^®-' all or part of his body to donees specified
by the statute. A body should include disorganized, homogenized fetal tissue
and an intact abortus or infant, as the distinction between them is only in the
manner of expulsion or extraction.^" Permissible donees include "any hospital,
surgeon, or physician for medical or dental education, research, advancement of
medical or dental science, therapy or transplantation ... or any accredited
medical or dental school, college, or university for education, research, advance-
ment of medical or dental science or therapy . . . . " i65 j would also include
private, nonprofit research organizations. Under the Massachusetts statute, a-
guardian may not give permission if the parent is "available" at the time of
death, '^^ and the act specifically states that the term "decedent" includes a
fetus or stillborn infant.-'^' Both the Massachusetts statute on Promotion of
Anatomical Science and the statute on fetal experimentation ^^^ permit a mother
of any age to consent to the research use of a dead fetus under specified limi-
tations, but the latter statute states that consent is not required in the case
of a routine pathological study and that, in a criminal proceeding, there shall
be a conclusive presumption of consent if it is in a written statement signed
by a mother at least eighteen years of age.-^^®
PROTECTIVE OR REGULATORY MECHANISMS
To recapitulate briefly, it is my recommendation that only innocuous, non-
therapeutic experimentation be allowed on beings with a potential for life, i.e.,
the previable fetus and the viable fetus. Where therapeutic research is neces-
sary for the health of either the fetus in utero or the mother, with a chance of
harm to the other, I suggest, in general, a careful balancing of the risks and
benefits to each party, with ultimate preference being given to the mother's
health and life, as she is the life in being. For the premature infant ex utero,
I recommend only therapeutic research. For the abortus, where in all but the
rarest instances death must ensue, I suggest that any reasonable nontherapeutic
research be permitted in the first six to eight weeks of gestation, that only
"justifiable" nontherapeutic research be permitted between six to eight and
eighteen weeks, and that only therapeutic research be permitted thereafter. In
my (admittedly untutored) view, the fetus becomes an abortus or premature infant
for purposes of determining the appropriateness of research when it is entirely
separated from the mother.
1. Child Protection Statutes
In the above scheme, the mother may consent to research on the fetus in
utero, and both parents--if the father is available — or a guardian may consent
to research on an abortus or premature infant. This society grants substantial
authority to parents to care for their children,^'" and it would be surprising
and inconsistent if this grant of authority did not extend to the fetus as well.
Therefore, the first mechanism to consider which may protect fetal inter-
ests is the general legal requirement that parents provide adequate care for
their children. The criminal codes of every jurisdiction in the United States
contain provisions prohibiting desertion or nonsupport of minor children, and
these statutes impose a duty upon parents or guardians to provide medical care.''"'
The typical nonsupport statute "... lays the foundation for a manslaughter
charge based on criminally negligent omissions should a child's death result
from inaction or neglect . . . ."1^2 Thus parents conceivably may be subject to
criminal penalties if they do not seek at least "ordinary" therapeutic experi-
mentation when all conventional measures to preserve the life or health of a
child have failed. '■'^ A court might construe a statute to extend this duty of
care to a fetus as well. The possibility of prosecution for failure to provide
such care is certainly no more unlikely than the pending "graverobbing" case in
Massachusetts .
14-21
"Cruelty to children" statutes may achieve the same result. Inaction
as well as action is frequently covered, i'" and their terms frequently include
deprivation of the necessities of life (such as medical care) and endangerment
of life, limb or health. ^'^ The Model Penal Code states: "A parent, guardian,
or other person supervising the welfare of a child under 18 commits a misdemeanor
if he knowingly endangers the child's welfare by violating a duty of care, pro-
tection or support. "^'^
In cruelty to children statutes, many states limit punishment to parents
or those standing in loco parentis.'^'''' Many states, on the other hand, say "any
person" may be punished, ^^^ and presumably, therefore, an attending physician
at an abortion procedure or normal birth might be covered. In any event, phy-
sicians, and even hospitals, may be liable under statutes requiring them to
report "child abuse," if they remain silent. ^■'^
The most commonly employed and the most commonly discussed protective
device is, of course, consent. Nevertheless, the issue of who is capable of
consenting to experimentation on a fetus is one of great difficulty. It is
similar to the question concerning who can consent to experimentation on chil-
dren or individuals who are mentally incompetent. Both classes of individuals
are incapable of consenting on their own behalf, and therefore proxy consent
must be obtained. '^°
In the case of children, there are no clear guidelines as to who may
consent for them. For purely therapeutic procedures it is the child's natural
guardians, his parents, who are given this power, •'^^ and the consent of one
parent is sufficient. Where a procedure is therapeutic but experimental or
innovative in nature, it again appears that a single parent may consent. But
problems arise in the area of nontherapeutic experimentation.
In the leading case on the subject, Bonner v. Moran,'^^^ a 15 year old boy
consented to be the donor in a skin transplantation procedure that was necessary
to save the life of his cousin. Although his aunt, the mother of the recipient,
was aware of his participation, his mother (at least at the outset) knew nothing
of the arrangement. The donor brought an action for assault and battery claiming
that his consent was insufficient to permit the physician to operate on him.
The trial court, following section 59 of the Restatement of Torts, instructed
the jury that if the plaintiff was capable of appreciating, and did appreciate,
the nature and consequences of the procedures and actually consented, then their
verdict must be for the defendant doctor. The jury returned a verdict for the
doctor .
After questioning the soundness of the general rule, the appeals court
pointed but that this procedure was not for the benefit of the plaintiff and that
it subjected him to substantial risk. The court then stated that in such circum-
stances the consent of the parent (not parents) is required. It thus appears
from this case that the consent of one parent is sufficient to enable a physician
to perform a procedure on a minor that is not for the benefit of that minor.
14-22
In the late 1950s the issue of parental consent for a nontherapeutic
procedure performed on a minor gained significance as a result of advances in
kidney transplantation. At that time several transplantation procedures had
been performed on adults but not minors. In 1957 three cases'^'' arose in
Massachusetts in which minors were to be used as donors in kidney transplant
cases. Counsel for the Peter Bent Brigham Hospital in Boston informed the hos-
pital that parental consent for the healthy minor was probably insufficient to
permit the surgery. This advice was based on two judicial opinions'^^ which
stated that a parent could not recover money paid to an infant upon his volun-
tary enlistment in the Armed Forces, in part because a parent could not require
a son to enlist in the Army against his wishes. On this basis, counsel reached
the conclusion that:
"If a parent has no power to make an effective decision regarding his
child's enlistment because of the hazardous nature of the service,
the conclusion seems inescapable that the parent likewise has no power
to give effective consent to an operation which is both hazardous and
personally detrimental to the child. "'^^
In the kidney cases the minors had all given their consent, and it does
not appear that the parents were forcing them to undergo operations. However,
as a result of counsel's advice, the hospital felt obliged to petition a single
justice of the Supreme Judicial Court to ratify the parents' consent. The Court
decided that each donor would receive a psychological benefit, and therefore the
parents could consent to the operations . ^^^
In a similar case, the Supreme Court of Kentucky allowed the transplanta-
tion of a kidney from an incompetent adult to his brother. ■'^^ This Court also
relied on the fact that the donor would receive a psychological benefit from the
donation; it also employed the doctrine of "substituted judgment" in which the
chancellor has the power to make decisions for an incompetent in the same manner
as the incompetent would, if he were competent. A dissenting opinion stated that
psychological benefit is not sufficient to allow a procedure that puts an incompe-
tent at peril.
Another recently developed transplantation procedure involves taking bone
marrow from a healthy sibling and transplanting it to a terminally ill sibling
in an attempt to cure the sick sibling. In earlier cases courts again utilized
the concept of psychological benefit, but recently a court specifically rejected
this test. ^^^ The Court found that "the evidence does not permit a finding that
the procedure will be of any benefit to [the donor]. "i*^ Pointing out that any
belief that the donor will receive a psychological benefit is mere speculation,
the Court said:
"If the sanctioning of a bone marrow transplant were to depend on the
finding of some benefit to the donor arising from it [sic] , allowance
or of some detriment to him or her if the sanction were denied, this
court would have to enter a judgment that the transplant proposed in
this case could not legally be performed since there is no such finding
with respect to [the donor] . This court does not believe that a
finding of benefit to the donor is essential ... To require a
finding of benefit to the donor, and particularly to accept a psy-
chological benefit as sufficient, often seems to invite testimony
conjured to satisfy the requirement by words but not by substance. " i^"
The court discussed and refused to utilize the substituted judgment doc-
trine. The opinion clearly stated that parents have "the right and responsi-
bility to make these decisions . . . ."'^iwith the safeguard of judicial review
to guard against a conflict arising from their responsibility to care for both
their children. The court must merely decide if the parents' decision to allow
their child to be a donor is "fair and reasonable. " ^^^
These cases, and a number of similar cases, teach us several lessons.
First, courts will allow parents to consent to the use of their children in
nontherapeutic procedures, if the benefits of the particular procedure (even
though not to the subject) outweigh the risks. In the bone marrow and kidney
transplant cases, the benefit (the possibility of saving a life) outv;eighed the
risk of possible physical harm to the donor. The risks are not insubstantial;
in kidney transplant cases the donor is subject to the risk of general anesthesia
(also true in the bone marrow cases) as well as the risk of living with only one
kidney. But in all of the kidney and bone marrow cases, a court has refused to
grant permission only once, and then on very narrow grounds. '^^ Second, courts
allow parents to place their children at serious risk where the child may derive
a benefit from it. One of the striking things about these cases is that the
courts never question the parents' right to consent to an experimental procedure
on behalf of the donee child. As this portion of the experimental procedure is
therapeutic (as opposed to the portion for the donor) , and since without the
procedure the child will die, the courts grant parents great latitude of choice.
Third, courts are very reluctant to second-guess parents after they have made a
decision concerning their child.
An unanswered question in these cases is whether both the mother and father
must consent to an experimental procedure which is not for the benefit of their
child. The question has not arisen because in all cases both parents have con-
sented. Had they not, it would nevertheless make sense to require the consent
of both, if both are available. Both run the risk of additional support if there
is damage to the donor child.''®'' I assume, moreover, that as the number of
individuals involved in protecting a child increases, the greater the protection
will be. The consent of both parents offers greater protection than the consent
of one, and an exception can be made in emergency situations.
For the most part the general principles stated above should be applicable
to fetuses. As I have attempted to demonstrate, however, the rules governing
fetal research should vary with the kind of research and the circumstances of
the fetus, i.e., viable or previable, in utero or ex utero. I shall therefore
discuss the doctrine of consent in these various situations.
14-24
(a) The Previable Fetus
I have argued previously that the fetus, as a being with a potential life,
should not be subjected to a nontherapeutic , experimental procedure. Even if
the mother plans an abortion, such research should be prohibited on the ground
that potential harm to the fetus may compromise her capacity to withdraw consent
to the abortion procedure. The kidney and bone marrow transplant cases are in
accordance with this position; in them a nontherapeutic procedure was permitted,
but only when this procedure was directly related to a lifesaving benefit to
another human being. I doubt that research on a fetus for the benefit of mankind
in general falls within the spirit of these cases, but, as is the case under the
Massachusetts statute on fetal experimentation,^'^ it is my view that the mother
should be permitted to consent to diagnostic procedures and to nontherapeutic
studies which do not substantially jeopardize the fetus.
There are times when therapeutic research is necessary for the mother which
may be detrimental to the fetus, and vice versa. Here we have a situation very
similar to the kidney and bone marrow transplant cases. A human being, the
mother, is intimately involved. She should be permitted to place the fetus at
risk if necessary to avert a substantial danger to her life or health. Because
the fetus is in utero , and her body is obviously involved in the most intimate
way in the experimental procedure, I would grant to her alone the right to con-
sent.-''® It would be necessary to modify this rule in emergencies, where consent
would be implied, and in cases such as unconsciousness where it might be neces-
sary to obtain the consent of next of kin or a guardian.
(b) The Viable Fetus
The viable fetus should have at least the status of the previable fetus,
and I recommend substantial protection for the latter. Here also, in my view
the fact that the fetus is within the mother's body gives her an overwhelming
interest which should not be subject to coercion from, or a veto by, the father.
(c) The Abortus
When the fetus is no longer inside the body of the mother, she has no
greater interest in it than does the father. Therapeutic experimentation per-
formed on a living abortus should, if possible, have the consent of both parents.
While there is a near certitude that the "child" will not live to leave the hos-
pital, if it survives for a few days, the expense may be great. Perhaps parents
need consent to only "ordinary," not extraordinary, research techniques. But as
"ordinary" techniques are perfected to increase the period of viability, the day
may come when an (apparent) abortus will live to become an infant. Both parents
should participate in a decision — even a decision made under legal compulsion —
of such financial magnitude.*'^
Of course if the abortus is dead it should be treated no differently than
a dead child or adult. Under the Uniform Anatomical Gift Act-"* a parent may
donate the body of his deceased child (including a fetus) for the purposes of
1 199
research.
14-25
(d) The Premature Infant
The general rules of consent for the use of therapeutic and innovative
procedures on a child should be followed here. However, in view of the pre-
carious condition of these infants, special precautions should be taken.
As a parting comment on the topic of consent, I assume it must be compe-
tent, voluntary, and knowledgeable. ^°° This may pose a problem for a mother,
or a mother and father, under 18. I am not insensitive to the fact that girls
in their early teens may bear children, and the girl or young father may be con-
fronted with decisions about research for which they have little mature judgment.
In such circumstances, perhaps for children under 15 or 16, the concurring con-
sent of an adult might be required for research on an abortus or premature infant;
but I would not remove the power of consent altogether from the young mother and
father. For research on a fetus, I would require the consent of a mother of any
age. This recommendation may be easier for me to make because I am opposed to
nontherapeutic research on a fetus. My basic feeling, however, is that even a
young mother is entitled to safeguard the sanctity of her own body, except pos-
sibly in situations of grave peril to herself or the fetus.
Review Committees
The proposed HEW regulations require an elaborate array of review commit-
tees. ^°^ No doubt review, by bringing many minds and different points of view
to bear, is useful in exposing hidden biases and in discovering potential perils.
It also may provide sufficient additional protection to permit consent by adoles-
cent parents. ^"^
Those who have suggested review committees have recommended that they
include physicians involved in research and those who are not,^°^ and individu-
als from all walks of life.^°* It has been suggested that review committees
not be associated in any way with the institution sponsoring research. ^°^ My
own experience on a committee to review grant applications involving research
on human subjects makes me somewhat pessimistic about the efficacy of lay repre-
sentation. ^"^ To perform an effective evaluation, many projects require techni-
cal expertise, and too many proposals of this sort dull an outsider's interest.
Having a technical review committee and a committee to review the ethical impli-
cations of different kinds of research is probably a good way to resolve the
dilemma, as long as bureaucratic inefficiency is avoided.
4 . Physician Advocate
Another protective device is to require two physicians to be present in
any research situation, one to perform research and the other to be responsible
for the patient. ^°^ The latter physician, who might be appointed to represent
a fetus, an abortus or a premature infant, would be responsible for protecting
his patient's best interest; he would communicate the progress of research
faithfully to the parents or guardian, make sure that consent is truly informed.
14-26
and require that every precaution be taken; he could withdraw his patient from
the research if the risk of harm became too great. ^°^ There would be a problem,
however, in the case of therapeutic experimentation. There the doctor performing
the research would also be clearly responsible for the patient's care, and the
presence of an additional, independent physician might constitute an unwarranted
interference with the first doctor's professional responsibility . ^°'
5. Compensation Fund
When fetal research is performed, parents or guardians may incur substan-
tial financial hardships. If nontherapeutic research in utero is permitted, it
may be very difficult to prove the chain of causation leading from the research
to a deformed infant. In these cases, therefore, it might be useful to consider
adopting a standard of liability without fault against the research investigator
in order to ensure the highest standard of care.^^°
For therapeutic research, however, such a standard would be too stringent.
The rules governing malpractice should apply, although they would have to be
modified with regard to proof of customary practice in the locality, as thera-
peutic research, by definition, is not customary . ^^^ Because an award of damages
for a deformed child might be crushing or unobtainable, it might be useful to
establish a compensation fund (perhaps through insurance) to protect doctors
from excessive claims and parents or guardians from long-term financial burdens.
Experimental methods to keep an abortus or premature infant alive may be
enormously expensive and impose a crushing economic hardship. Faced with this
possibility, a doctor might be tempted to diminish his efforts, and parents
might be tempted to demand less of him. ^'^ This would be a cruel choice, in
particular for poor, inner-city residents. Therefore, in addition to ensuring
a fair distribution of costs in the case of malpractice, a compensation fund
might be used to assist parents where no negligence is present. ^■'^ The promise
of some assistance in paying for in-hospital expenses and postnatal care at
home might help to stimulate the most vigorous yet responsible research efforts
by members of the medical profession engaged in fetal research.
14-27
REFERENCES
1. Reinhold, "Boston and the Doctors: Strange Case," New York Times, April 21,
1974, at sec. 4, p. 11 [hereinafter cited as "Strange Case"].
2. Idem.
3. Boston Globe, Feb. 3, 1975, at 2.
4. Mitchell, "The Child and Experimental Medicine," British Medical Journal,
722, 725-26, 1964. For a score of examples of recent lapses in medical
ethics see J. Katz, Experimentation with Human Beings, 9 and 307-310, 1972,
reprinting Beecher, "Ethics and Clinical Research," New England Journal
of Medicine 274:1354, 1966. See also "Panel Discusses Ethics of Studies
on Humans — Especially the Poor," Journal of the American Medical Associa-
tion 231:233, 1975.
5. Kemp, "The Battered Child and the Hospital," Hospital Practice, Oct. 1969,
at 44.
5. Note, "Fetal Experimentation: Moral, Legal, and Medical Implications,"
Stanford Law Review 26:1191, 1195, 1974 [hereinafter cited as "Stanford
Fetal Experimentation Note"].
7. Boston Globe, May 12, 1974, at 1.
8. Boston Globe, Feb. 15, 1975, at 24.
9. Letter to the Editor from John F. Enders, New England Journal of Medicine
290:1199, 1974.
10. Interview with James H. Staton, Executive Director, Boston Hospital for
Women, Division of Affiliated Hospital Center, Boston, Mass., in Boston,
Feb. 19, 1975 [hereinafter cited as "Staton Interview"].
11. Boston Globe, Feb. 15, 1975, at 3.
12. "Staton Interview," note 10 supra.
13. "Stanford Fetal Experimentation Note," note 6 supra, at 1192.
14. Interview with Dr. David Nathan, Children's Hospital Medical Center, Boston,
Mass., in Boston, Feb. 13, 1975 [hereinafter cited as "Nathan Interview"].
15. Bender, D. , Problems of Death 34, Anoka, Minnesota: Greenhaven Press, 1974..
14-28
REFERENCES (Continued)
16. "Stanford Fetal Experimentation Note," note 6 supra, at 1194.
17. Boston Globe, note 11 supra.
18. Idem.
19. "Staton Interview," note 10 supra.
20. Boston Globe, note 11 supra.
21. Parker et al., "The Impact of Liberalized Abortion Law in New York City on
Deaths Associated with Pregnancy: A Two Year Experience," Bulletin of
New York Academy of Medicine 49:804-18, 1973.
22. Mass. G.L.A., ch. 46, §9.
23. "Staton Interview," note 10 supra.
24. Roe V. Wade, 410 U.S. 113 (1973).
25. Idem. , at 164-65.
26. Idem, at 153.
27. Idem, at 153.
28. Idem, at 163.
29. Idem, at 162.
30. Idem, at 162-65.
31. Idem, at 158.
32. Idem, at 157.
33. Idem, at 162.
34. Idem, at 163-64.
35. Idem, at 160. ■ •
36. Idem, (citation omitted).
37. Idem, at 158.
38. Idem, at 160-61.
39. Idem, at 159. ■ '
14-29
REFERENCES (Continued)
40. Unlike Shakespeare's Second Apparition in Macbeth, the Court most certainly
did not intend to exclude from the class of "born" persons those who from
their mothers' wombs were "untimely ripped" (Act IV, Scene VIII) by
Caesarian section.
41. "[A]t common law ... the whole body of the child must be extruded before it
becomes a person." Paton, A Text-Book of Jurisprudence 354, 3d ed., 1964.
42 . "The earlier cases . . . required a complete separation of the infant from the
mother and the establishment of an independent circulatory existence [for
infanticide] . In the relatively later cases it has been held however that
severance of the umbilical cord is not requisite to establish such condi-
tion." Singleton v. State 35 So. 2d 375, 378 (Cal. 1948).
43. Philipson, Sabath, and Charles, "Transplacental Passage of Erythromycin and
Clindamycin," New England Journal of Medicine 288:1219, 1973.
44. "Strange Case," note 1 supra.
45. Boston Globe, Feb. 16, 1975, at 5.
46. Boston Globe, Feb. 17, 1975, at 32.
47. Boston Globe, Feb. 16, 1975, at 4.
48. Idem.
49. Idem.
50. Idem.
51. Idem.
52. Boston Globe, note 46 supra.
53. Idem.
54. DHEW, "Proposed Rules, Protection of Human Subjects," Federal Register
39:30648, Aug. 23, 1974.
55. Idem, at 30653, §46.303.
56. Note, "Experimentation on Human Beings," Stanford Law Review 20:99, 1967
[hereinafter cited as "Stanford Human Experimentation Note"] .
57. Idem, at 101.
58. Ely, "The Wages of Crying Wolf: A Comment on Roe v. Wade," Yale L.J.
82:920, 1973 [hereinafter cited as "Ely"].
14-30
REFERENCES (Continued)
59. Idem, at 935-36 (footnotes omitted).
60. Idem, at 940. Lochner v. New York, 198 U.S. 45 (1905). :
61. "Ely," note 58 supra, at 948.
62. Tribe, "The Supreme Court, 1972 Term, Foreword: Toward a Model of Roles in
the Due Process of Life and Law," Harvard Law Review 87:1, 15-32, 1973
[hereinafter cited as "Tribe"].
63. Idem, at 21.
64. Idem, at 19.
65. Idem, at 23-25.
66. Idem, at 29. ' ' - ■■ . •
57. McGowan v. Maryland, 366 U.S. 420 (1961); Two Guys from Harrison-Allentown,
Inc. V. McGinley, 366 U.S. 582 (1961). See also Gallagher v. Crown Kosher
Super Market of Mass., Inc., 366 U.S. 617 (1961) and Braunfeld v. Brown,
366 U.S. 599 (1961) .
68. "Ely," note 58 supra, at 926.
69. 410 U.S. at 158.
70. Marbury v. Madison, 1 Cranch 137, 2 L. Ed. 60 (1803).
71. 32 Mass. (15 Pick.) 255 (1834).
72. "In its mother's womb," Black's Law Dictionary 619, rev. 4th ed. 1968.
73. E.g., Crowles v. Crowles, 56 Conn. 240, 13 A. 414 (1887); In re Laird,
85 Pa. 339 (1877) .
74. Black's Law Dictionary 619, rev. 4th ed. 1968, citing 1 Bl. Comm. 130.
75. Paton, G. , A Text-Book of Jurisprudence 354, 3d ed . 1964. See also Roe
V. Wade, note 24 supra, at 162.
76. Roe V. Wade, 410 U.S. 113, at 132 (citation omitted).
77. Perkins, Criminal Law 27, 1957; American Jurisprudence 40, 2d, Homicide,
§9, at 300-01; C.J.S. 40, Homicide, §2, at 825; Means, "The Law of New
York Concerning Abortion and the Status of the Foetus, 1664-1958: A
Case of Cessation of Constitutionality," N.Y.L. Forum 14:411, 1968;
Annot. , 159 ALR 523.
REFERENCES (Continued)
78. Bracton's The Laws and Customs of England, quoted by Means, "The Law of New
York...," note 77 supra, at 419 represents a 13th century description of
English law: "If there be anyone who strikes a pregnant woman or gives
her a poison whereby he causes an abortion, if the foetus be already
formed or animated, and especially if it be animated, he commits homicide."
79. "If a woman be quick with child, and by a potion or otherwise killeth it in
her wombe , or if a man beateth her whereby the childe dyeth in her body,
and she is delivered of a dead childe, this is a great misprision, and no
murder; but if the childe be born alive and dyeth of the potion, battery,
or other cause, this is murder; for in law it is accounted a reasonable
creature, in rerum natura, when it is born alive." Sir Edward Coke,
Institutes III *50, 1648, as quoted by Means, "The Law of New York...,"
note 77 supra, at 420.
80. American Jurisprudence 40, 2d, Homicide, §9, at 300-01; Annot., ALR 40, 3d,
446, §2. See also People v. Harper, 300 N.Y. 171 (1949) and Singleton v.
State, 33 Ala. App. 536, 35 So. 2d 375 (1948). "'Person,' when referring
to the victim of a homicide, means a human being who has been born and is
alive." New York Penal Law, §125.05 (1).
81. See People v. Chavez, 77 Cal. App. 621, 176 P. 2d 92 (1947).
82. Evans v. People, 49 N.Y. 86 (1872); Foster v. State, 182 Wis. 298, 196 N.W.
233 (1923).
83. "' [M]oment of conception' is a figment of the imagination, since conception
like everything else is a process which takes time." Williams, "The
Legalization of Medical Abortion," The Eugenics Review 19, April 1964, at
21, as cited by Brodie , "The New Biology and the Prenatal Child," J. Earn.
Law 9:391, 1970, at 391, n. 2. Also, conception is "a 'process' over time,
rather than an event...," Roe v. Wade, note 24 supra, at 161, citing a
number of "new biology" articles.
84. State v. Atwood, 54 Ore. 526, 102 P. 295 (1909), reh. 54 Ore. 542, 104 P.
195 (1909); State v. Elliott, 207 Ore. 82, 289 P. 2d 1075 (1955).
85. 138 Mass. 14 (1884) .
86. Idem, at 17.
87. 184 111. 359, 56 N.E. 638 (1900), overruled, Amann v. Faidy, 415 111. 422,
114 N.E. 2d 412 (1953) .
88. Annot., 15 ALR 3d 992, 994.
89. Prosser, Handbook of the Law of Torts 355-6, 3d ed. 1964, [hereinafter
cited as "Prosser"].
14-32
REFERENCES (Continued)
90. Prosser, in 1964, listed Alabama, Rhode Island, and Texas as the only
jurisdictions not yet permitting recovery for prenatal injuries. Idem,
at 356. Since 1964, Rhode Island (Sylvia v. Gobeille, 220 A. 2d 222
(1966)) and Texas (Leal v. Pitts Sand and Gravel, 419 S.W.2d 820 (1967))
appear to have abandoned the old rule.
91. "Prosser," note 89 supra, lists only nine jurisdictions (Cal., Ga., 111.,
La., Mich., N.H., N. J. , Pa., and Wis.) as having discarded the "viability"
and "quickening" requirements. It appears that New York (Kelly v. Gregory,
282 App. Div. 542, 125 N.Y.S.2d 696 (1953)) should have been included in
his compilation. And, since Prosser 's 1964 survey, Rhode Island (Sylvia
V. Gobeille, 220 A. 2d 222 (1966)), Texas (Delgado v. Yandel, 468 S.W.2d
475 (Tex. Civ. App. Tex.)), and possibly Massachusetts (Torigian v.
Watertown News Co., 352 Mass. 446, 225 N.E.2d 926 (1967) (viability test
discarded, no reference to quickening requirement)) have joined the list.
92. See, e.g., Leccese v. McDonough, 279 N.E.2d 339 (Mass. 1972); Henry v. Jones,
306 F.Supp. 726 (D. Mass. 1969).
93. 21 of the 22 jurisdictions permitting, the 12 jurisdictions denying, and the
2 jurisdictions which have recently permitted a wrongful death action where
there has been a live birth but have expressly reserved decision on the
stillbirth situation are listed in Note, "Damages for the Wrongful Death
of a Fetus — Proof of Fetal Viability,..," Chicago - Kent Law Review 51:1
227, 1974, at 228-9, no. 17. The Note lists Alabama as a state reserving
decision, but in September 1974, Alabama joined those states permitting
such an action. Eich v. Town of Gulf Shores, 8 Ala. B. Rep. 2075
(Sept. 12, 1974), reviewed in Cumberland - Samford Law Review 5:362, 1974.
94. Porter v. Lassiter, 91 Ga. App. 712, 87 S.E.2d 100 (1955).
95. Enacted as part of the Social Security Act of 1935, 42 U.S.C., sees. 601-10
(Supp. II, 1972) .
96. Note, "Statutory and Constitutional Bases for Extending AFDC Benefits to
Families with Unborn Children," Southern California Law Review 48:121,
130, 1974, [hereinafter cited as "AFDC Note"].
97. 42 U.S.C. sec. 607 (a) (1970).
98. 45 C.F.R. sec. 233.90 (c) (2) (ii) (1973).
99. "AFDC Note," note 96 supra, at 124-5 (several footnotes abbreviated or
omitted) .
100. Idem, at 137-9.
101. Parks v. Harden, 354 F.Supp. 620, 622 (N.D. Ga. 1973), as quoted in "AFDC
Note," note 96 supra, at 151.
14-33
REFERENCES (Continued)
102. 43 U.S.L.W. 3409 (U.S. Jan. 28, 1975).
103. Alcala v. Burns, 326 F.Supp. 180 (S.D. Iowa 1973), aff'd 494 F.2d 743 (8th
Cir. 1974) cert, granted, 43 U.S.L.W. 3187; oral arguments heard Jan. 22,
1975, 43 U.S.L.W. 3409 (U.S. Jan. 28, 1975). [The Supreme Court rendered
a decision shortly after this paper was submitted. On the basis of
statutory analysis, it held that the unborn are not dependent children.]
104. Raleigh Fitkin-Paul Memorial Hospital v. Anderson, 42 N.J. 421, 201 A. 2d
537 (1964), cert, denied 377 U.S. 95 (1964).
105. Idem, 201 A. 2d at 538. See also In re Sampson, 55 Misc. 2d 658, 317 N.Y.S.
2d 641 (1970), aff'd 37 App. Div. 2d 658, 323 N.Y.S. 2d 253, aff'd 29
N.Y.2d 900, 278 N.E.2d 918 (1972).
106. 410 U.S. at 163-4.
107. Mass. G.L.A. ch . 112, §12J.
108. See In re Smith, 16 Md. App. 209, 295 A. 2d 238 (1972). But see Application
of President and Directors of Georgetown College, Inc., 118 D.C. App. 8,
331 F.2d 1000, 9 ALR3d 1367, reh en banc denied, 118 D.C. App. 8, 331
F.2d 1010, cert, denied, 377 U.S. 978 (1964) (blood transfusion).
109. 410 U.S. at 163-4.
110. "[G]eneral usage and modern understanding of the word 'health' ... includes
psychological as well as physical well-being." U.S. v. Vuitch, 402 U.S.
62, 72 (1971) .
111. Maine Medical Center v. House, Sup. Ct. Cumberland Cnty., Maine, No. 74-145
(Feb. 14, 1974) (unreported opinion. Judge David Roberts). Case noted in
Knox, "Defective Newborns: Life or Death Issue," Boston Globe, Mar. 10,
1974, at A-1. See also Annas, G., The Rights of Hospital Patients, New
York, New York: Discus, 79-87, 1975.
112. E.g., California Health and Safety Code, §25956.
113. 138 Mass. 14 (1884) .
114. "Nathan Interview," note 14 supra.
115. Foote, C; Levy, R. ; and Sander, F.; Cases and Materials on Family Law,
480, 1966.
115. "Nathan Interview," note 14 supra.
117. Idem.
REFERENCES (Continued)
118. It has been reported that a team of doctors led by Dr. Geoffrey Dawes and
Dr. Kenneth Boddy of Oxford, England has shown, through the use of ultra-
sound, that about thirteen weeks after conception fetuses being to
"'breathe' in the womb. Not only that, [some] also gasp, sigh, cough,
and hiccup as well." Johnson, Lawrence H. , Science Editor #1112, at 3,
University of California, April 9, 1974.
119. See, e.g., Mass. G.L.A. ch. 229, §6.
120. 8A C.J.S., Animals, §99; Mass. S.P.C.A. v. Comm. of Public Health, 339 Mass.
216, 228 (1957); N.J. S.P.C.A. v. Board of Education, 219 A. 2d 200, aff'd
227 A. 2d 506 (1966) .
121. E.g., 111. Rev. Stat. ch. 8, §221; Iowa Code Ann. §717.3; Mass. G.L.A. ch.
272, §75; Tenn. Code Ann. §39-404.
122. Comm. v. Turner, 145 Mass. 296 (1887); Comm. v. Higgins, 227 Mass. 191 (1931);
8A C.J.S., Animals, §99.
123. Mass. G.L.A. ch. 49A, §2. See also Mass. S.P.C.A. v. Comm. of Public Health,
339 Mass. 216, 228 (1957) .
124. 8A C.J.S., Animals, §101. But see N.J. S.P.C.A. v. Board of Education, 219
A. 2d 200, aff'd 227 A. 2d 506 (1966).
125. Mass. G.L.A. ch. 49A, §2.
126. Idem.
127. See, e.g., Mass. G.L.A. ch . 49A, §8A.
128. "Ely," note 58 supra, at 926.
129. 410 U.S. at 157-58.
130. In re Sampson, 65 Misc. 2d 658, 317 N.Y.S.2d 641 (1970), aff'd 37 App. Div.
2d 668, 323 N.Y.S.2d 253, aff'd 29 N.Y.2d 900, 278 N.E.2d 918 (1972).
See also the fetal research statutes of 111., Ind., Ky., Me., Mass., Minn.,
Nebr., Ohio, Pa., and Utah, set forth in the Appendix.
131. But see American Medical Association, Ethical Guidelines for Clinical
Investigation, Opinions and Reports of the Judicial Council, Chicago:
A.M. A., 9-11, 1969; Editors, "Judgment Difficult," New England Journal
of Medicine 269:479, 1962.
132. 402 U.S. 62 (1971) .
14-35
REFERENCES (Continued)
133. Brief and Appendices of Dr. Bart Heffernan, Amicus Curiae in Support of
Appellant, U.S. v. Vuitch, 402 U.S. 62 (1971), at 4.
134. Idem, at 27-33 (footnotes omitted) .
135. Idem, at 15.
136. "Tribe," note 62 supra, at 19-20 (footnotes omitted).
137. Idem, at 21.
138. Roe V. Wade, 410 U.S. 113, at 159.
139. Bok, "Ethical Problems of Abortion," The Hastings Center Studies 2:33, 41,
1974, [hereinafter cited as "Bok"].
140. Idem, at 43.
141. Boston Globe, Feb. 11, 1975, at 10.
142. Boston Globe, Feb. 6, 1975, at 15.
143. Boston Globe, Feb. 12, 1975, at 8.
144. Boston Globe, note 142 supra.
145. "Bok," note 139 supra, at 44.
146. Idem, at 37.
147. Idem, at 51.
148. "Stanford Fetal Experimentation Note," note 6 supra, at 1199.
149. La. Rev. Stat., Title 14, Sec. 87.2 (Acts 1973, No. 77, Sec. 1); Maine Rev.
Stat., Ann., Title 22, Sec. 1574-76 (Acts 1973, Chapt. 518, Sec. 3-5).
150. Black's Law Dictionary 488, rev. 4th ed. 1968. See also Thomas v. Anderson,
215 P. 2d 478 (1950) .
151. See "A Definition of Irreversible Coma: Report of the Ad Hoc Committee of
the Harvard Medical School to Examine the Definition of Brain Death,"
Journal of the Americal Medical Association 255:337, Aug. 5, 1968.
152. Handbook of the National Conference of Commissioners on Uniform State Laws,
1968, Appendix 293 [hereinafter cited as "Handbook"]; Sadler and Sadler^
"Providing Cadaver Organs: Three Legal Alternatives," The Hastings
Center Studies 1:15, 1973, [hereinafter cited as "Sadler"].
14-36
REFERENCES (Continued)
153. Mass. G.L.A. ch. 113, §13(b). The Comment following Sect. 7 of the Uniform
Anatomical Gift Act, "Handbook," note 152 supra, states: "Subsection (b)
leaves the determination of the time of death to the attending or certifying
physician. No attempt is made to define the uncertain point in time when
life terminates. This point is not subject to clear cut definition and
medical authorities are currently working toward a consensus on the matter.
Modern methods of cardiac pacing, artificial respiration, artificial blood
circulation and cardiac stimulation can continue certain bodily systems
and metabolism far beyond spontaneous limits. The real question is when
have irreversible changes taken place that preclude return to normal brain
activity and self sustaining bodily functions. No reasonable statutory
definition is possible. The answer depends upon many variables, differing
from case to case. Reliance must be placed upon the judgment of the
physician in attendance. The Uniform Act so provides.
154. Mass. G.L.A. ch. 113, §13(b).
155. "Handbook," note 152 supra, at 192.
156. Idem (emphasis added).
157. N.Y. Public Health Law, Title V, §4160 (effective Sept. 1974).
158. Idem, at §4164 (1) .
159. Idem, at §4164 (2) .
160. Idaho Code §18-608 (3) (Supp. 1973); Utah Code Ann. §76-7-309 (Supp. 1973).
161. See generally Annot., 54 ALR3d 1043-6.
162. Doe V. Doe, No. 1105-6 (Mass. Sup. Jud. Ct., July 3, 1974) (Hennessey dissent),
citing Spock, Baby and Child Care, 28-31 (Rev. Pocket Book ed. 1968) and
Wright, The New Childbirth, 158-90 (Pocket Book ed. 1971).
163. Mass. G.L.A. ch. 113, §§8 (a) and (b) .
164. "Stanford Fetal Experimentation Note," note 6 supra, at 1203.
165. Mass. G.L.A. Ch. 113, §9.
166. Idem, at §8 (a) .
167. Idem, at §7(b) .
168. Mass. G.L.A. ch. 112, §12J.
169. Idem.
14-37
REFERENCES (Continued)
170. See Kleinfeld, "The Balance of Power Among Infants, Their Parents, and the
State," Part II, Parental Power, Family L. Q. 4:409, 1970.
171. Paulsen, "The Legal Framework for Child Protection," Columbia Law Review
66:679, 689-90, 1966 [hereinafter cited as "Paulsen"].
172. Idem, at 690.
173. Idem, at 684.
174. Idem.
175. Idem, at 682.
176. Uniform Laws Annotated, Model Penal Code, at 568, §230.4, (West 1974).
177. "Paulsen," note 171 supra, at 683.
178. Idem.
179. Idem, at 712.
180. "Prosser," note 89 supra, at 103.
181. Zoski V. Gaines, 271 Mich. 1, 260 N.W. 99 (1939); Moss v. Rishworth, 222
S.W. 225 (Tex. 1920); "Prosser," note 89 supra, at 104.
182. 126 F.2d 121 (D.C. Cir. 1941).
183. Masden v. Harrison, 68651 Eq. Mass. Sup. Jud. Ct., June 12, 1957; Huskey v.
Harrison, 58666 Eq. Mass. Sup. Jud. Ct. , Aug. 30, 1957; Fostor v. Harrison,
68674 Eq. Mass. Sup. Jud. Ct . , Nov. 20, 1957. See Curran, "A Problem of
Consent: Kidney Transplantation in Minors," New York University Law Review
34:891, 1959.
184. Banks v. Conant, 14 Allan 497 (Mass. 1867); Taylor v. Mechanics Savings
Bank, 97 Mass. 345 (1867).
185. Katz, J., Experimentation with Human Beings, 966, 1972 [hereinafter cited
as "Katz"] .
186. Idem, at 972.
187. Strunk v. Strunk, 445 S.W. 2d 145 (Ky. 1969).
188. Nathan v. Farinelli, No. 74-87 Eq. Mass. Sup. Jud. Ct., July 3, 1974.
189. Idem, at 3.
14-38
REFERENCES (Continued) ;. •-
190. Idem, at 7-8.
191. Idem, at 10.
192. Idem, at 11.
193. In re Richardson, 284 So. 2d 185 (La. 1973).
194. In his concurring opinion in Lacey v. Laird, 166 Ohio St. 40, 139 N.E.2d
25 (1956) , Justice Hart states that the requirement of parental consent
to medical procedures is "based upon the right of the parents whose
liability for support and maintenance of their child may be greatly
increased by an unfavorable result of the operational processes...."
Idem, at 139 N.E.2d 30.
195. Mass. G.L.A., ch. 112, §12J.
196. "Staton Interview," note 10 supra, describing policy at Boston Hospital
for Women.
197. See generally Robertson, "Involuntary Euthanasia of Defective Newborns:
A Legal Analysis," Stanford Law Review 27:213, 1973.
198. "Handbook" and "Sadler," note 152 supra.
199. Idem. Interestingly, under a statute recently passed in Illinois, parental
donation of a dead fetus may not be permitted. 111. Grim. Law and Procedure
38 §81-18 states that all "tissue" removed at the time of the abortion must
be examined by a pathologist. It goes on to say "There shall be no exploi-
tation of or experimentation with the aborted tissue." As a matter of
policy it makes no sense to treat a dead fetus differently from a dead
adult.
200. Kaimowitz v. Dept. of Mental Health for the State of Michigan, Civ. Action
No. 73-19434-AW (Cir. Ct. for Cnty. of Wayne 1973).
201. DHEW, "Proposed Rules, Protection of Human Subjects," Federal Register
39:30648, 30653-54, Aug. 23, 1974.
202. See Calabresi, "Reflections on Medical Experimentation in Humans," Daedalus
98:2:387, 403, Spring 1969 [hereinafter cited as "Calabresi"].
203. Lewis, McCollum, Schwartz, and Grunt, "Informed Consent in Pediatric
Research," Children 16:143, 148, 1969, reprinted in "Katz," note 185
supra, at 994.
204. "Stanford Human Experimentation Note," note 56 supra, at 109.
14-39
REFERENCES (Continued)
205. Idem.
206. This view is voiced by others: "Nathan Interview," note 14 supra;
"Stanford Human Experimentation Note," note 56 supra, at 109.
207. "Stanford Human Experimentation Note," note 56 supra, at 109; Wall Street
Journal, April 14, 1971, at 1 and 17, reprinted in "Katz," note 185
supra, at 997-98.
208. Idem.
209. "Stanford Human Experimentation Note," note 56 supra, at 109.
210. Idem, at 115.
211. Karp v. Cooley, 349 F.Supp. 827 (S.D. Tex. 1972), aff'd 493 F.2d 408 (5th
Cir. 1974).
212. Note, however, that at least thirteen states now have statutes requiring
that measures be taken to save viable fetuses. Family Planning/Population
Reporter 3:5:92, Oct. 1974. "The inability to distinguish postviability
fetacide from infanticide, and hence the state's power to prohibit both,
may entail serious hardships for the woman or family involved.... But
our society does not regard killing as an acceptable remedy." "Tribe,"
note 62 supra, at 28, n. 128. For discussions of the ethical problem
of withholding treatment from children, see Duff and Campbell, "Moral
and Ethical Dilemmas in the Special-Care Nursery," New England Journal
of Medicine 289:890, 1973, and Shaw, "Dilemmas of the 'Informed Consent'
in Children," New England Journal of Medicine 289:885, 1973.
213. See "Calabresi," note 202 supra, at 395. See also Nathan v. Farinelli,
No. 74-87 Eq. Mass. Sup. Jud. Ct., July 3, 1974, at 12; Note, "Medical
Experiment Insurance," Columbia Law Review 70:965, 1970.
14-40
APPENDIX
In this appendix I set forth commentary about various state statutes
governing fetal experimentation.
1) California - Health and Safety Code, Sec. 25960
California has two identically numbered sections dealing with fetal experi-
mentation. The wording of the two sections is almost identical. One section
prohibits experimentation on any "aborted product of conception" and the other
prohibits experimentation on any "aborted product of human conception . . . ."
Experimentation to "protect or preserve the life and health of the fetus" is not
prohibited. Experimentation on "fetal remains" which is defined as "a lifeless
product of conception" is also not prohibited. A fetus is lifeless if there is
no "discernible heartbeat."
There is no prohibition on experimentation in utero.
2) Illinois - Criminal Law and Procedure 38 § 81-18
All tissue removed at the time of abortion must be submitted to a patholo-
gist. The statute goes on to say "There shall be no exploition of or experimen-
tation with the aborted tissue." There is no distinction made between living
and dead "tissue." There is no prohibition of experimentation in utero.
Since one can assume that live fetuses are not sent to the pathologist,
as a matter of interpretation this section must be concerned with tissue from
dead fetuses. Thus, it appears that experimentation on dead fetuses is outlawed
but experimentation on live fetuses is not, which makes this a rather unusual
provision.
3) Kentucky - Crimes and Punishments - 436.026
The sale, transfer, distribution or giving away of any "live or viable
aborted child" is prohibited. Whoever "permits" such child to be used for any
form of experimentation is also guilty of a crime. Thus, penalties would apply
to parents as well as the experimenter if the parent consents to the experimen-
tation. There is no exception for experiments designed to preserve the life or
health of the aborted "child." There is no prohibition of in utero experimenta-
tion. The minimum sentence under the statute is 10 years.
4) Louisiana - Revised Statutes, Title 14 § 87.2
Experimentation on a human embryo or fetus in utero is prohibited unless
it is to preserve the life or improve the health of the embryo or fetus.
"Human experimentation" on any "live born human being" without the consent
of that human being is prohibited if done without the consent of that human being,
unless it is done to protect or preserve his life or health. Under the statute,
a human being is live born if it is expelled or extracted from its mother, and
breathes or shows other evidence of life such as a beating heart, pulsation of
the umbilical cord or movement of voluntary muscles, whether or not the umbilical
cord has been cut or the placenta is attached, and irrespective of the duration
of pregnancy.
The breadth of this statute is enormous since it applies to everyone who
is alive, regardless of age. We are all "live born human beings." This statute,
besides banning fetal experimentation, also bans experimentation on children and
mental incompetents who cannot consent for themselves.
Experimentation without consent is made a crime punishable by a minimum
sentence of 5 years at hard labor and a maximum or 20 years. An experimenter
who fails to obtain adequate informed consent from an adult subject could be
siibjected to punishment.
5) Maine - Maine Revised Statutes, Title 22, Sec. 1574-1576
Any live human fetus, whether intrauterine or extrauterine, or any live
born product of conception, may not be used, transferred, distributed or given
away for the purpose of scientific experimentation. The definition of live born
is essentially the same as that used in Louisiana. Maine's use of the term "any
live born product of conception" includes everyone who is now alive. In effect,
it prohibits the "use" of any human being for human experimentation, regardless
of consent. This ban would seem to include experimentation for the purpose of
preserving the life or health of the fetus, or anyone else.
6) Massachusetts - Massachusetts General Laws, Ch. 112 § 12J
Live human fetuses, whether before or after expulsion from the womb, may
not be used for scientific, laboratory, research, or other kind of experimenta-
tion. Procedures "incident to the study" of the fetus in utero are not prohib-
ited if in the physician's judgment the study will not "substantially jeopardize"
the life or health of the fetus, and the fetus is not the subject of a planned
abortion. The use of the word "study" probably indicates that it is something
other than "experimentation" that is permitted. Perhaps the mere observation of
the fetus is what the draftsman had in mind. ^ ,
Diagnostic or remedial procedures to determine or preserve the life or
health of the fetus or mother are specifically permitted. It is not clear if
this includes experimental diagnostic or remedial procedures.
A fetus is live when, in the medical judgment of the physician, "it shows
evidence of life as determined by the same medical standards as are used in evi-
dence of life in a spontaneously aborted fetus at approximately the same stage
of gestational development." . i ,
A dead fetus can be experimented on with the mother's consent.
The word fetus includes embryos and neonates.
7) Minnesota - Public Health Laws § 145.38 •, :/ ■
"Human conceptus" means a human organism, conceived either inside or out-
side the human body, from fertilization through 265 days thereafter.
"Living" means "the presence of evidence of life, such as movement, heart
or respiratory activity, the presence of electroencephalographic or electrocar-
diographic activity."
Experimentation on a live conceptus is prohibited, except to protect the
life or health of the conceptus. However, research on such a conceptus is per-
mitted if "verifiable scientific evidence" has shown that the research is "harm-
less. "
This statute established what appears to be a definite cutoff point after
which experimentation is not regulated, since the exact date of conception is
difficult, if not impossible, to ascertain. As a practical matter experimenters
will probably use the 265 day figure as a rough guideline.
The legislature also tried to permit harmless experiments. But one doubts
if any experiment on such a subject is absolutely harmless, and one also wonders
what is "verifiable scientific evidence."
8) Missouri - H.C.S. Bill No. 1211 (unclassified 1974 laws)
No person shall use any fetus or premature infant aborted live for
experimentation. This applies to fetuses in utero and after abortion.
Experiments on a "premature infant" born alive to preserve its "life and
health" (emphasis added) are permitted. Apparently, experimental procedures to
protect the life or health of the fetus in utero are prohibited.
9) Montana - Criminal Code 94-5-617
"Premature infants" born alive may not be used for scientific research or
experimentation unless it is for the purpose of protecting the life and health
of such premature infant. In utero experimentation is not regulated.
10) Nebraska - Revised Statutes § 28-4,161
The sale, transfer, distribution or giving away of a live or viable
"aborted child" for the purpose of experimentation is prohibited. Any person
who consents to, aids or abets such sale or transfer is also guilty of a crime.
The experimentation itself does not appear to be prohibited. One who
veceives such an "aborted child," however, might be guilty of aiding or abetting
the transfer. If the mother consents to the transfer, she would also be guilty
of a crime. No exception is made for experiments that would preserve the life
or health of the "aborted child." In utero experimentation is not regulated.
11) New York - Public Health Law § 4164
New York's statute does not actually deal with experimentation. It states
that any viable "child" which results from an abortion is accorded immediate
legal protection under the laws of New York. It would thus be treated as any
other child for purposes of experimentation.
12) Ohio - Am. Sub. House Bill 989 §2919.14
"No person shall experiment upon or sell the product of human conception
which is aborted." No exception is made for experiments to preserve the life
or health of the aborted fetus. Both dead and live fetuses are similarly treated.
In utero experimentation is not regulated.
13) Pennsylvania - Session Laws 1974, Act 209, § 5
Same as Montana
14) South Dakota - Public Health and Safety 34-23A-1
"Experimentation with fetuses without written consent of the woman shall
be prohibited." Apparently both living and dead fetuses, in utero and after
abortion, may be used for experimentation as long as the mother consents.
It is interesting to note that if the woman is a minor, her parent, or
husband if married, must consent to the abortion. It appears, however, that a
minor woman can consent to fetal experimentation on her own.
15) Utah - Criminal Code 76-7-310 to 311
Live "unborn children" may not be used for experimentation. They may be
tested for genetic defects. No exception is made for experiments to preserve
the life or health of the "child." There is no prohibition against experimen-
tation on the "child" after an abortion.
15) Indiana - Criminal Code vol. 2, Part 2, Sees. 10-112
Indiana's statute on fetal experimentation is not discussed herein, as it
was not available for analysis.
14-44
15
AN ASSESSMENT OF THE ROLE OF RESEARCH
INVOLViNG LIVING HUMAN FETUSES
IN ADVANCES IN MEDICAL SCIENCE AND TECHNOLOGY
BATTELLE-COLUMBUS STAFF CONTRIBUTING TO THIS REPORT INCLUDE:
Dr
R.
1.
Leininger, Principal Investigator
Dr
Samuel Globe, Technical Advisor
Dr
D.
A.
Axler, Congenital Rubella Syndrome
Dr
L.
F.
Harris, Congenital Rubella Syndrome
Dr
A.
D
Barker, Isoimmunization
Dr
A.
J.
Dennis, Isoimmunization
Dr
R.
D
Falb, Respiratory Distress Syndrome
Dr
W
T
McComis, Respiratory Distress Syndrome
Dr
D
L.
Gardner, Amniocentesis
Mr
B
R
Lower, Amniocentesis
Dr
R
L.
Bernstine, Battelle Human Affairs Research Center
Seattle
Med
cal Advisor
Mi
ss e
. A
. Frautschi, Information Science
Dr
A
M
Pfefferle, Columbus, Ohio, Animal Models
N01-
HU
-5-2122
Contents
SUMMARY 15-1
INTRODUCTION • 15-2
OVERALL CONCLUSIONS AS TO THE NEED FOR FETAL RESEARCH 15-3
METHODOLOGY 15-6
CASE STUDIES
CONGENITAL RUBELLA SYNDROME (RUBELLA VACCINE) 15-9
Medical Significance ■ 15-9
Historical Account 15-10
Contribution of Human Fetal Research to the Development
of the Rubella Vaccine 15-13
Effect of a Retrospective Ban on Fetal Research 15-15
Future Outlook - 15-15
References 15-17
Principals Interviewed 15-21
AMNIOCENTESIS 15-25
Medical Significance 15-25
Historical Account ' 15-35
Contribution of Human Fetal Research to Amniocentesis ■ 15-39
Effect of Retrospective Ban on Human Fetal Research on
Amniocentesis ■ 15-41
Outlook for Amniocentesis as a Clinical Procedure 15-44
References ... 15-46
Principals Interviewed 15-54
ISOIMMUNIZATION (Rh VACCINE) . 15-57
Medical Significance 15-57
Historical Account 15-59
Contribution of Human Fetal Research to the Control of
Rh Hemolytic Isoimmune Disease 15-62
Effect of a Retrospective Ban on Human Fetal Research
on the Control of Rh Isoimmune Hemolytic Disease 15-64
Future Outlook 15-67
References . 15-68
Principals Interviewed 15-71
Contents (continued)
RESPIRATORY DISTRESS SYNDROME (RDS) 15-75
Medical Significance 15-75
Historical Account 15-77
Contribution of Fetal Research to RDS 15-84
Effect of a Retrospective Ban on Fetal Research 15-85
Future Outlook 15-86
References 15-87
Principals Interviewed 15-94
ANIMAL MODELS
ANIMAL MODELS ' • 15-97
Introduction and Summary 15-97
Congenital Rubella Syndrome 15-99
Amniocentesis , . 15-105
Isoimmunization 15-117
Respiratory Distress Syndrome 15-12 3
GLOSSARY 15-131
APPENDIX
DISCUSSION OF THE PROCEDURE AND COMPLICATIONS OF AMNIOCENTESIS 15-139
Technique 15-139
Timing of the Procedure 15-141
Complications 15-142
Amniography, Ultrasonography, Amnioscopy and Fetoscopy 15-145
An Assessment of the Role of Research
Involving Living Human Fetuses
In Advances in Medical Science and Technology
A study has been made of four important developments in the combined area
of fetology-neonatology-pediatrics-obstetrics with emphasis on the assessment of
the role of research involving living human fetuses in the evolution of these
developments. The cases chosen for study were: amniocentesis, congenital
rubella syndrome (rubella vaccine) , Rh isoimmunization (Rh vaccine and therapeu-
tic exchange transfusions), and respiratory distress syndrome.
As in other scientific or technical developments, progress occurred through
essentially discrete paths of research which, however, were mutually reinforcing
and which led to a significant advance in medical science. Detailed accounts
and historiographs of each case were developed and these are presented in later
sections .
Research in each of these cases involved both animal models and living
human fetuses to varying degrees and in varying ratios. Later sections discuss
in some detail the estimated effects that a ban on research on living human
fetuses would have had on each development. Briefly stated here, adequate ani-
mal models were not available at the times needed and only in isoimmunization
has appreciable progress since been made towards an adequate model. Thus, the
developments would have been halted indefinitely, except perhaps for the Rh
vaccine which would have been delayed for at least five, and more probably ten
years. Also very recently progress has been made towards a model useful for
respiratory lung distress.
With the benefit of retrospection, it is concluded that investigators pro-
ceeded to clinical trials with very high ratios of benefit to risk in each case.
The benefits have indeed been high — rubella and Rh vaccines can eliminate fetal,
neonatal and later mortality and morbidity caused by rubella, and Rh incompati-
bility in the expectant mother. Prior to the development of the Rh vaccine,
multiple exchange transfusions were developed for effective therapy of both the
fetus and the neonate. Consequent social and economic gains are obvious. In
the case of rubella, the National Foundation-March of Dimes estimated that the
number of cases of rubella and congenital rubella syndrome in the United States
dropped 57 percent to 11,836 cases in 1974, compared to 1973. In the prevaccine
years 1966-68, the number of cases was 47,500 per year. The gains resulting
from the treatment or prevention of Rh isoimmune hemolytic disease are also
great. It is estimated that the annual number of stillbirths resulting from
the disease was 10,000 before the development of the therapeutic and prophylac-
tic methods. The in utero exchange transfusions alone can rescue 50 percent of
15-1
these fetuses. It is estimated that pre- and postnatal exchange transfusions
have saved 200,000 lives in the period between 1940 and 1960. The development
of the Rh vaccine can prevent the disease in an estimated 25,000 infants at
risk each year in the United States. In the case of respiratory distress syn-
drome, the gains are not yet so dramatic, but advances in the understanding of
the disease and its detection have led to both prophylactic and therapeutic
approaches of great promise. Amniocentesis has made major contributions to the
other cases and, moreover, has led to a wide range of diagnostic procedures
which for the first time allow the assessment of fetal health and development
in utero.
INTRODUCTION
Advances in embryology and fetology combined with advances in genetics,
immunology, virology, cell biology, and other disciplines have resulted in
procedures and treatment that enable :
(1) Diagnosis in utero of ntimerous genetic, developmental, or
teratogenetic defects.
(2) Reduction or elimination of certain of the risks of such
defects to the embryo, fetus, or infant.
The development of such procedures has involved research on living human
fetuses and is related to the larger subject of research on living humans.
This matter has become of such importance that a National Commission for the
Protection of Human Subjects of Biomedical and Behavioral Research* was estab-
lished in 1974 by the United States Congress. At the time of its establishment,
a moratorium was instituted on HEW support of nontherapeutic research on living
human fetuses before or after induced abortions.** The National Commission was
charged with recommending to the Secretary of Health, Education and Welfare by
April 30, 1975 whether this moratorium on research on living human fetuses
should be continued, lifted, or modified.
To furnish background information on which to base its recommendations,
the National Commission contracted with the Columbus Laboratories of Battelle
Memorial Institute to make an assessment of the role of research involving
living human fetuses in certain advances in medical science and technology.
The advances to be considered were:
(1) Congenital Rubella Syndrome (Rubella Vaccine)
(2) Amniocentesis
♦Hereinafter referred to as the "National Commission.
**Public Law 93-348, Section 213.
15-2
(3) Isoimmunization (Rh Vaccine)
(4) Respiratory Distress Syndrome.
Of these cases, amniocentesis is a general technique that makes possible a
wide range of diagnostic procedures; congenital rubella syndrome and isoimmuni-
zation are concerned primarily with the prevention of defects; and respiratory
distress syndrome is concerned with the prior warning and treatment or preven-
tion of a very serious neonatal problem.
Each case was to be studied retrospectively and the significant steps lead-
ing to the final procedure were to be identified. The use of living human fetuses
in the course of the reseatch was to be studied intensively and, most importantly,
the impact of the substitution of other procedures for living human fetuses was
to be projected as far as possible. That is, an attempt would be made to answer
the question. What would be the estimated effects of such substitution on (a) the
time to develop the procedures; (b) changes in morbidity and mortality; (c) eco-
nomic costs; and (d) related scientific advances?
While these were the objectives of the program, both the National Commission
and Battelle-Columbus recognized that the time available (from February 4, 1975,
to the March 7, 1975, submission of the draft report) would impose limitations.
The following sections describe the methodology used, the four individual
cases, and the overall conclusions drawn from the four cases. Although the
report is intended for the informed layman, the use of medical and scientific
terms was unavoidable. Therefore, a glossary of technical terms has been pro-
vided.
In this report the term "research on living fetuses"* embraces any experi-
mentation on either the pregnant woman or the fetus in which either drugs or
surgical procedures are involved. The "fetal period"* is to be understood as
the time from implantation to delivery, including the first seven to eight
weeks, which are usually referred to as embryonic.
OVERALL CONCLUSIONS AS TO THE NEED FOR FETAL RESEARCH
It is apparent from a study of the development of the four selected cases,
amniocentesis, isoimmunization, respiratory distress syndrome, and congenital
rubella syndrome, that research on living human fetuses played a significant
role in each. The concern here is the estimation of the probable effect that
a ban on research involving the use of living human fetuses would have had on
the course of these developments. The phrase "research on living human fetuses"
has been defined* as any research done on either the pregnant woman or the living
fetus, or in short, any experimentation that could perturb the living fetus or
its environment. To carry such a restriction to the ultimate would, of course.
""These definitions supplied by the staff of the National Commission.
15-3
prevent new therapeutic, prophylactic, or diagnostic procedures for fetuses or
pregnant women from reaching clinical usage. First clinical trials would con-
stitute such research and thus be automatically proscribed. In light of this,
we have considered fetal research as somewhat analogous to the accepted method
of drug development. New drugs are evaluated in animal models as to toxicity
and efficacy to the point where it is felt by competent judges that clinical
trials are warranted. The risk involved in this final step is dependent upon
the adequacy of the subjective judgment and of the animal model used. No amount
of animal use will insure complete safety in first clinical trials if the animal
models do not very closely mimic the human siibjects. Thus the four developments
studied here must be considered with regard to the availability of adequate
animal models for the several lines of research and the multiple steps in each
for the different cases. In effect, this study has focused on the possibility
of greater use of animal models and the consequences of this change in each of
the developments.
Although "cases" are being studied here, it must be noted that each was
composed of several parallel efforts that were mutually reinforcing and which
together led to an advance in a diagnostic method or treatment or prevention of
a disease state. Thus a procedural change or delay in one contributing research
approach could have a profound effect on the total development. This is true
even in what appears to be an independent development. For example, amniocen-
tesis had its origin in 1882 as a palliative procedure for the treatment of
polyhydramnios. Over the years it was found that the amniotic fluid withdrawn
in the procedure could furnish much information as to the health of the fetus
and allow the identification and measurement of the progression of many fetal
disorders. This later use of the procedure contributed significantly to the
understanding and eventual prophylaxis or treatment of two of the cases studied
here, Rh isoimmunization and respiratory distress syndrome. This procedure,
obtaining amniotic fluid, is unique among the developments studied in that no
record was found of preceding animal studies. Since its first use, there have
been many animal studies — primarily to determine suitability of the animals as
fetal models — but no animals have been found to be adequate as models for the
technique itself. A detailed exposition of the model shortcomings may be found
in the section on amniocentesis .
With the other cases, which are concerned with therapeutic and prophylactic
procedures, adequate animal models were also unavailable. In congenital rubella
syndrome, once the association between rubella in the gravid human and the con-
genital defects was established, preparation of the vaccine could be thought to
be straightforward. However, no animal is known which could have shown that the
attenuated live virus vaccine given to a pregnant woman would traverse the pla-
centa to infect the fetus, and that it is therefore necessary that the vaccine
be administered well before pregnancy.
In respiratory distress syndrome, amniocentesis was essential in obtaining
human amniotic fluid which would allow the determination of the vital lecithin/
sphingomyelin ratio that measures the fetal lung maturation. The effect of
corticosteroids was widely studied in various animals, but the animal models
were deficient because of a placental barrier to the drug that is absent in the
human, and because the lung-surfactant system is different. It should be noted
15-4
that this steriodal hormone treatment is still experimental. Considerable
further research is necessary and a valid mother-placenta-fetus model is not
yet known. A more recent treatment for respiratory distress syndrome is the
administration of plasminogen to the neonate. Promising results have been
obtained but its ultimate effectiveness cannot yet be assessed. Rationale for
the treatment was based on a knowledge of the etiology of the disease but,
given the etiology, development of the treatment did not involve research on
living human fetuses. Prior determination of the probable occurrence of the
disease by determination of the L/S ratio through amniocentesis would give
warning that treatment would be needed.
In Rh isoimmunization, again use of both animals and living human fetuses
is found. As in the respiratory distress syndrome, amniocentesis is found to
be central to research leading to an understanding, characterization, and
detection of the disease. Both animal and living human fetal research were
involved in the steps leading to therapy (transfusions) and prophylaxis (Rh
vaccine). These animal models also were deficient, as is described later, and
research involving living human fetuses was necessary to reach definitive con-
clusions. Today the course of research could be different — in the mid-1960s,
intensive research began on the isoantigens of lower primates and the mechanism
of isoimmune disease in these animals. It is conceivable that the use of these
animals could have eliminated some of the use of living human fetuses, but the
Rh vaccine was developed before the animal models became available. Interrup-
tion of the Rh isoimmunization study in order to wait for the primate research
would have delayed the development of Rh vaccine accordingly. It is doubtful
and even improbable that the risks to the eventual clinical subjects would have
been appreciably decreased by the added primate work.
Special attention should be paid to the place of amniocentesis. As noted,
this procedure went into clinical use without prior animal studies, and even
after more than 90 years, no adequate animal model has been found. Had the ban
on fetal research been in effect, amniocentesis would not be used today. The
importance of amniocentesis in the research leading to prevention or treatment
of respiratory distress syndrome and Rh isoimmune hemolytic disease cannot be
overstated. Not only does amniocentesis enable detection and monitoring of the
progression of the diseases in utero, but its use was vital in characterizing
the diseases and the etiologies. Without this basic knowledge, there would
have been no basis for the successful research directed towards prevention or
cure. Postnatal- transfusions for Rh hemolytic disease were begun before the
basic knowledge was gained, but they, of course, do not apply to stillborns,
nor do they prevent prenatal damage.
Thus the conclusion is reached that in the four cases studied, adequate
animal models were not available and--with the exception of Rh isoimmunization —
the prospect of adequate models becoming available is small. As in the case of
therapeutic drugs, dependence must be placed on the judgment of qualified per-
sons that proceeding to research involving living human fetuses is justified on
the basis of risk/benefit considerations.
Because of the current interest, instances of fetal research can also be
classified as to "therapeutic" or "nontherapeutic" application. That is, the
15-5
procedure was defined according to the objective either of aiding the individual
fetus involved or of gaining knowledge that would contribute to the well-being of
fetuses in the future. The findings follow:
Congenital Rubella Syndrome (Rubella Vaccine)
The fetal research here involved fetuses whose abortions were planned.
The objective was to determine if the vaccine given to the pregnant
mother would infect the fetus. Thus it was for the benefit of future
fetuses and is classified as nontherapeutic.
Amniocentesis
In respiratory distress syndrome, amniocentesis contributed to both
therapeutic and nontherapeutic fetal research, as will be seen in
those sections. Fetal research involving amniocentesis has led to
methods that can diagnose fetal abnormalities. Because at this
time remedies for a large majority of these abnormalities are not
known, most of this research must be classified as nontherapeutic
to the subject fetus. It should be noted, however, that the pro-
cedures can be of immediate therapeutic benefit to the pregnant
mother.
Isoimmunization (Rh Vaccine)
Early fetal research here had the dual objectives of detecting and
characterizing the disease in the fetus. Detection would give prior
warning that an exchange transfusion would be necessary. Research
directed towards characterization, while of benefit to future
fetuses, would also identify those at risk and thus be of immediate
therapeutic value. Intrauterine exchange transfusions were initiated
as a direct therapeutic measure.
Respiratory Distress Syndrome
Fetal research directed toward detection of the impending disease
is classified as therapeutic because it showed the need for delay
of the delivery or the need for postnatal treatment. In fetal
research involving steroids, the first (1961) was to determine if
Cortisol administered to pregnant women would cross the placenta.
This is classified as nontherapeutic. In the other steroid fetal
research, the objective was the development of therapy that would
benefit the fetus involved and so is therapeutic.
METHODOLOGY
The methodology was in general derived from that used in the Battelle study
for the National Science Foundation on the interactions of science and technology
in the innovative process.* In that study the objectives included the identification
♦"Interactions of Science and Technology in the Innovative Process: Some Case
Studies," Final Report by Battelle, Columbus Laboratories to National Science
Foundation, Contract NSF-C667, March 19, 1973.
15-6
and characterization of significant and decisive events, and assessment of their
importance to the innovative process. Any general or qualitative characteristics
that were common to the eight cases of innovation were also identified.
In the present program primary concern was the significant steps in each of
the four cases that were found to include, as an essential element, research on
living fetuses. These steps were then studied in detail to estimate the effects
of substitution of animal models (or perhaps in vitro methods) for living human
fetuses .
Thus the project proceeded chronologically as follows:
1. Construction of an historical outline of the development of each
case, showing the chronology of the steps contributing to the
development of the clinical procedure or treatment. These are
described in the narratives and in diagrammatic form in the
sections on the individual cases.
2. Identification of the significant steps and determination of
those in which living human fetuses were used in the research.
3. Estimation of the effects of a delay in research on living human
fetuses, and evaluation of the possibility of alternate pathways.
The latter could include the use of animal models or in vitro
methods .
4. Comparison of the probable progress and final results from the
use of alternate routes as compared with the actual path involv-
ing the use of living human fetuses.
5. Assessment of the significance of the development.
6. Determination of any general conclusions or principles that are
suggested by the foregoing assessments.
To carry out this study, an interdisciplinary team was assembled which
included case leaders from disciplines appropriate to each case, supported by
other life scientists, information scientists, librarians, and various consul-
tants and advisers. Management of the program, because of its interdisciplinary
nature, was provided by members of the Research Council of Battelle-Columbus.
After definition of the program and organization, the initial step was the
literature searches in each of the four cases. Initially, machine searches were
performed at the National Library of Medicine, as arranged by Dr. Duane Alexander
of the National Commission and Miss Charlotte Kenter of the National Library of
Medicine. These searches included MEDLARS II from January 1972 to the present,
CATLINE from 1964 to the present, and BACKFILE from January 1969 to September
1971. Many of the articles, books, and reports listed in the search results
15-7
were obtained through local libraries. A review of these publications identified
many references to earlier work. Concurrently, searches were made of local
sources at Battelle, The Ohio State University School of Medicine, and hospital
libraries by the project staff, including an information scientist.
Because of the pressure of time, the National Commission recommended the
use of a number of consultants who were active participants or knowledgeable in
the various fields. These consultants were expected to supply not only infor-
mation from personal experience, but also references to other work. Scheduling
difficulties resulting from the short time available prevented optimum utiliza-
tion of this group. In addition, other experts both in Columbus and elsewhere
were consulted.
Further aid in gathering information to be analyzed was given by an
obstetrician-gynecologist of the Human Affairs Research Center of Battelle
Memorial Institute in Seattle, and by a Columbus geneticist, serving as a
research associate to the project.
Concurrently with the literature search, analysis proceeded to identify
and describe the significant steps in each case. The analyses, literature
search, and inputs from the consultants were mutually reinforcing throughout
the project.
Throughout the project, meetings were held among the groups to insure
commonality of methods and objectives, and to identify features and conclusions
common to the subgroups. Overall conclusions drawn from this study therefore
represent a consensus of the project team.
Each of the cases is reported separately in the following sections. For
each case, the significance of the development to the mother and fetus (or neo-
nate) is described. Important steps in each development are described narra-
tively and shown in an historiograph. These latter show the steps in the
characterization, etiology, and detection of the disease states and the devel-
opment of therapeutic or prophylactic procedures. In the case of amniocentesis,
the history and applications of the procedure are shown. In each historiograph,
the steps are coded to show the experimental animal involved.
Although the events are shown chronologically, it is not implied that each
event was a direct consequence of the preceding. Arrows were used to show
dependence on a previous finding. Also, the listing of an event and the senior
author is not to be taken as showing absolute priority for a given development.
Time did not allow rigorous establishment of priority. The historiographs do
show the paths of the developments and the place of research involving living
human fetuses in the overall history.
Because of the importance of animal models to this study, further and more
detailed information was obtained and combined with the information found in
each case study to form an additional section of the report. This furnishes
additional bases for the conclusions reached in this study.
CASE STUDIES
CONGENITAL RUBELLA SYNDROME (RUBELLA VACCINE)
Medical Significance
In discussing the medical significance of congenital rubella, several
points need to be made.
(1) Congenital rubella is a disease that involves many body
organs and results in a wide range of defects. The phy-
sical findings are often accompanied by a variety of
behavioral manifestations.
For proper management of the multihandicapped rubella
child, facilities are required that go beyond just the
deaf or deaf-blind child for which they are currently
designed. Facilities are needed to deal with the mul-
tiple problems that may arise with certain children.
(2) Congenital rubella is not only a multisystem disease,
but a continuing disease. Therefore, long-term eval-
uations are necessary so that defects not evident at . .
birth are not overlooked and so that the etiology of
later problems can be identified.
(3) Mental retardation is a major consequence of congenital
rubella. In one study, ^ 37 percent of infected chil-
dren had varying degrees of retardation. This figure
is remarkable when one considers that the expected
prevalence in the general population is 2 to 3 percent.
(4) To the families of rubella children, the disease has a
powerful psychological and social impact. The presence
of a rubella child has an effect on the entire family
and their way of life.
It is clear that congenital rubella has a profound effect both on the
affected child and the family. The need, therefore, to protect the pregnant
female from infection by the use of appropriate vaccines is pressing. To this
end, rubella vaccines have been available since 1969, and what follows is an
indication of their effectiveness. Questions remaining to be answered regarding
vaccine effectiveness are described in the section entitled "Outlook."
Riibella first became a nationally notifiable disease in 1966, when all
states agreed to submit a weekly report to the Center for Disease Control (CDC)
of the number of reported cases of rubella.
15-9
Congenital rubella syndrome (CRS) also became a notifiable disease in
1966. The National Registry for Congenital Rubella Syndrome was established
in 1969 for the collection and analysis of detailed- reports on all reported
cases.
With the licensing of live, attenuated rubella virus vaccine in 1969,
large-scale immunization campaigns were carried out in the United States to
control r\ibella and, therefore, prevent the occurrence of congenital rubella
syndrome. Prior to 1969, epidemiologic studies showed that rubella occurred
primarily in young children who, in turn, were the primary source of infection
for pregnant women. 62 The Public Health Service Advisory Committee on Immuni-
zation Practices** and the Committee on Infectious Diseases of the American
Academy of Pediatrics ^ recommended vaccination of prepubertal children on a
large-scale basis, reducing virus transmission and preventing congenital rubella,
in short not subjecting adult women to the risks of intensive vaccination.
Since the introduction of the rubella vaccine into widespread use, the
number of reported cases of rubella decreased steadily from 1969 (57,686 cases)
to 1972 (25,501 cases), the lowest yearly figure since the beginning of nation-
wide reporting. In 1973, 27,901 cases were reported to the CDC (9.5 percent
over 1972) . Most of the 1973 increase occurred in the first 28 weeks of the
year with reports for the remainder of 1973 falling to 50 percent below those
of the previous year. This downward trend has continued through the first
10 months of 1974 with a decrease of 60 percent below the corresponding period
in 1973.
Since the introduction of the rubella vaccine, the number of reported CRS
cases has declined since 1969. For the first 12 months following vaccine admin-
istrations, approximately 91 cases of CRS were reported. Over the next three
12-month periods, there were 54, 40, and 25 cases of CRS reported to the National
Registry for Congenital Rubella Syndrome.
The steady decline over the past four years of reported rubella and congen-
ital rubella syndrome cases is testimony and justification for the research on
rubella virus disease that culminated in the development of several live attenu-
ated vaccines. Although the results of the last four years are encouraging, only
careful surveillance for rubella and CRS will reveal whether childhood vaccination
programs continue to be effective in interrupting transmission of disease to preg-
nant women and in reducing fetal wastage and congenital malformations.
Historical Accoimt
Clinical Studies of Rubella and the Congenital Rubella Syndrome
Rubella was first described as a disease entity by de Bergen in 1752.
The disease was reported to be distinct from measles by Veale in 1866.®° Rubella
in children and adults is generally characterized as a mild exanthem which rarely
15-10
produces complications. However, as the result of an epidemic of rubella in
Australia in 1939-1940, an unusual number of cases of congenital cataract were
observed from areas throughout Australia. These findings prompted Norman Gregg
in 1941^' to conduct retrospective studies which associated for the first time
maternal rubella with congenital malformations.
Shortly after Gregg's report two large-scale investigations were conducted
in Australia. Swan et al.,49 studied congenital defects in neonates in southern
Australia; in New South Wales a committee was appointed by the Director General
of Health to investigate Gregg's observations. These investigations confimned
and expanded the original findings. The major congenital defects found were
deaf-mutism, eye and heart disease, and possible mental defectiveness. In
addition, there was evidence that the type of defect was related to the time
when maternal rubella occurred; the highest risk was in the first trimester of
pregnancy.
Following the original reports by the Australians, observers in other
countries reported similar findings. Investigators approached the subject from
different viewpoints according to their own specialities. Carruthers (1945)
reported on severe deafness in the neonate.^ Dogramaci and Green (1947)
described congenital heart disease. i^ In 1949, Kamerbee reported on progressive
deafness in the neonate, ^^ and Mutrux observed retarded myelinization as an
effect of congenital rubella. ^^ Other investigators have studied the short-term
and prolonged effects of congenital rubella in regard to temporal bone involve-
ment 3° and cataracts and neurological damage. ^^
The United States epidemic of rubella in 1953-1965 confirmed and expanded
on the defects observed previously. Rudolph et al. , described heart and eye
defects.** Severe neurological disturbance was identified by Desmond et al. , and
in 1973, Rorke"*' described ischemic brain damage resulting from congenital riibella.
Isolation, Identification, and Association of Rubella with Congenital
Rubella Syndrome
The focus on rubella began with Gregg's observations in 1941 associating
maternal rubella with congenital abnormalities. The development of laboratory
techniques permitting specific diagnosis of rubella, however, did not occur until
some 20 years later. The rubella virus was isolated in 1962, independently, by
Weller and Neva^i using human amnion cell culture and Parkman and associates'^*
using African green monkey kidney cells. Subsequently in vitro studies by
Plotkin'** and Rawles"^ have shown that rubella-virus-infected cells undergo
mitotic inhibition and chromosome breakage.
Selzer,*° and Alford et al. ,i were successful in isolating rubella virus
from human fetal tissue, demonstrating for the first time a definitive etiologic
agent of the congenital rubella syndrome. Monif and Sever ^5 reported that rubella
virus could be isolated from a variety of clinical specimens, including throat
swabs, rectal swabs, cerebrospinal fluid, liver biopsy, and urine. In addition,
several investigators 2°' ^^^ ■**' ** have isolated rubella virus from the lens of the
eye of congenitally infected fetuses. Hambridge et al.,20 reported that infants
with congenital rubella syndrome excrete rubella virus in the urine for many
months after birth, creating a potential source of contact infection.
Following the isolation of rubella virus in cell cultures, serological
techniques to detect immunity to rubella were rapidly developed. Parkman
et al.,40 described a virus neutralization test for detection of serum antibody.
It was shown that following infection with rubella virus, neutralizing antibodies
developed which persisted indefinitely conveying a high order of protection
against reinfection. Other diagnostic serological techniques have also been
described. Brown et al.,^ demonstrated that antibodies to rubella virus could be
detected by the imm\mo fluorescence test. Sever et al.,^^ described a complement-
fixation test for detection of immunity to ri±iella. A most significant finding
was reported by Stewart et al.,^'' that rubella virus would agglutinate erythro-
cytes (hemagglutination) and that antibody to the virus would inhibit hemagglu-
tination. As with neutralizing antibodies, hemagglutination-inhibition (HAD
antibodies appear at the end of the first week after symptoms of rubella, reaching
peak levels 10-21 days after onset and persist indefinitely. Consequently, for
diagnostic purposes, an acute serum sample is obtained at onset of symptoms, and
after two weeks a convalescent serum sample is obtained. A fourfold rise in anti-
body titer is diagnostic. During the years 1967-1969, several independent inves-
tigators "• ^^^ ^^^ ^^^ ^^ conducted comparative studies of diagnostic techniques for
detection of r\±iella. As a result, the HAI test has largely replaced the neutral-
ization, complement fixation, and immunofluorescence tests for determining immu-
nity status to rubella.
Tondury^s reported that the placenta plays a role in maternal- fetal trans-
mission of rubella. These observations were confirmed by Singer^^ and extended
by Hancock, 21 who described the development of antibodies of the IgM type in the
newborn resulting from in utero infection. In considering the diagnostic impli-
cation of this finding, it is significant to note that antibodies of maternal
origin which cross the placenta are of the IgG type and the IgM antibody is of
fetal origin. Both IgG and IgM antibodies can be measured by the HAI test.
During the early postnatal months, the transplacentally acquired IgG is lost;
however, IgM production is continued. Therefore, the persistence of HAI anti-
bodies (IgM) through the first year of life supports the diagnosis of congenital
rubella.
A significant refinement of the HAI test was described by Cooper et al.^"
They found that heparin-manganese chloride treatment of sera would remove non-
specific inhibitors of rubella hemagglutination allowing a reliable detection
of HAI antibodies.
In 1970, the Center for Disease Control (CDC) recognized the need for
standardizing the rubella HAI test, and consequently formulated a standard pro-
tocol for the performance of the test based upon comparative studies among
several laboratories.^
Development of Vaccines
Following the isolation of rubella virus, impetus was provided to develop
a vaccine. Since rubella is generally a mild illness, the principal objective
of the vaccine is to prevent infection of the fetus and the resulting congenital
rubella syndrome.
In 1965, Parkman, Meyer, and associates^s attenuated rubella virus by 77
serial passages in primary African green monkey kidney (GMK) cell culture
(HPV-77) . The first clinical vaccine trials were by Meyer et al.j^i using HPV-77
rubella strain as a vaccine. Subsequently, other attenuated rubella strains have
been derived from HPV-77, among which are HPV-77 passaged five times in duck
embryo fibroblast cell culture (HPV-77DE5) and HPV-77 passaged 12 times in dog
kidney cell culture (HPV-77DK]^2) • ^^ addition, an attenuated rubella virus
strain (Cendehill) passaged 51 times in primary rabbit kidney cell culture has
been developed.
Experimental animal models for studies of rubella have not been particu-
larly rewarding, although congenital infection can be induced in the rhesus
monkey .i"' '*! Prior to licensing of live attenuated rubella vaccine in 1969,
studies were conducted in the rhesus monkey. The findings were that the vaccine
virus did not cross the placenta. ,
Subsequent vaccine trials using HPV-77 rubella strain derivatives and
Cendehill strain have demonstrated that attenuated rubella vaccines do confer
seroconversion in approximately 95 percent of vaccinees. However, it is now
apparent that, contrary to the findings in rhesus monkeys, attenuated rubella
vaccine virus can cross the placenta and infect the human fetus. Vaccine virus
has been recovered from fetal tissue after accidental vaccination of pregnant
women 1^' 28, 42 and purposeful inoculation of vaccine virus in women about to
undergo planned abortions.'*' ^^ ^ . ;
In 1971, the United States Public Health Service initiated a "Herd Immunity"
program. Because, in an epidemiological sense, children represent the major
"herd" of susceptibles that the virus requires to maintain itself, a general
inoculation of children ranging in age from one year to puberty was initiated.
However, outbreaks continued with cases in other un vaccinated age groups. An
epidemic occurred in 1971 in Casper, Wyoming, involving 1,039 persons primarily
in two high schools and three junior high schools. ^^ These findings have prompted
several authors to propose that the concept of herd immunity is invalid, and that
outbreaks among adolescents and adults demonstrate the inadequacy of childhood
vaccination.^' 25, 26 _, .
Contribution of Human Fetal Research to the
Development of the Rubella Vaccine
Antecedent to the development of the rubella vaccine was the isolation of
riibella virus in African green monkey cells in culture. With the inherent risk
15-13
to the fetus if infected with the wild-type virus, it was necessary to attenuate
the virus so that the immunizing properties of the virus would be retained while
at the same time eliminating the potential biohazardous nature of the rubella
virus .
The initial association between rubella virus infection in utero and the
development of congenital defects was derived from retrospective studies. The
first definitive relationship between in utero rubella infection and what is
termed the congenital rubella syndrome (CBS) , occurred in 1963 when Selzer was
able to isolate virus from fetal tissue. so The involvement of the virus during
gestation was expanded with the description of both the role of the placenta in
maternal- fetal transmission by Tondury in 1966^* and the isolation of IgM anti-
bodies in the newborn by Hancock in 1968.^^ It became clear, therefore, that
infection by rubella virus during early pregnancy could result in transplacental
passage of the virus with siibsequent infection of the fetus. In utero infection
could then result in one or a number of congenital defects observable at or sev-
eral years after birth. This information could have been obtained only from
studies of the gravid female and fetal tissue.
As mentioned in the first paragraph, although the vaccine for rubella is
attenuated, it is still live. It, therefore, may still be hazardous to a sus-
ceptible fetus. To examine this possibility, the use of an experimental animal
model system would be ideal, so that the experimental work and associated risk
to humans would be unnecessary. To this end, the rhesus monkey was used. As
with the human, infection with wild-type virus of the pregnant rhesus monkey
results in transplacental passage of the virus with subsequent infection of the
fetus. However, infection of the pregnant rhesus monkey with attenuated vaccine
virus did not cross the placenta and, consequently, did not infect the fetus.
If there is to be any value derived from an animal model system, the information
should be able to be extrapolated to the human situation. However, a case has
been reported by Phillips et al., in 1970, ^^ of a young woman who discovered she
was pregnant following voluntary entrance into a vaccination program. The vac-
cine was given at approximately three weeks gestation and the pregnancy terminated
at eight weeks. Rubella was successfully isolated from the decidua. Subsequently,
purposeful inoculation of pregnant women about to undergo planned abortions "*• ^^
and accidental vaccination of pregnant women '^'^^ have resulted in recovery of
vaccine virus from fetal tissue.
It appears, therefore, that reliance solely on information from animal
model systems could lull one into a false feeling of security. One is forced
to realize that the only way to either understand the biological behavior of a
virus in hiomans or assess the risk to humans associated with vaccination, is to
perform the studies in humans.
Had the fortuitous, accidental inoculation of pregnant women not been done
and had the results from the rhesus monkey studies been used to conclude the
safety of the vaccine in the pregnant female, exposure of pregnant women might
have had tragic consequences for fetuses otherwise destined for normal, uncompli-
cated development.
15-14
Effect of a Retrospective Ban on Fetal Research
From what has been discussed previously, human fetal research has been
central to an understanding of the biological behavior of rubella virus and in
the definitive association between in utero rubella infection and congenital
abnormalities. Beyond this, it would have been impossible to define the rela-
tionship between gestational age and the consequences of rubella infection with-
out human studies. There is no animal model system in which the development of
the fetus in terms of size and function relationships is comparable to the hianan
model .
By the use of the rhesus monkey, the potential teratogenic activity of the
rubella virus vaccine was masked. This potential was realized only when the
virus vaccine was administered accidentally to pregnant women or intentionally
to pregnant women about to undergo planned abortion.
Also, because IgM antibody does not cross the placenta, the demonstration
of IgM specific for rubella virus in cord serum indicated an immune response by
the fetus following direct exposure to the rubella virus. This finding and its
correlation with potential congenital rubella syndrome could have been made only
by an analysis of the human model.
Although vaccine development could have been accomplished without the use
of human subjects, the need for its development would have never been recognized
without the human studies that definitively linked in utero rubella infection
with congenital abnormalities.
It would be unfair if one did not concede that there are animal model sys-
tems for a variety of general viral infections, and that they themselves teach
some remarkable biology. However, it would be equally unfair and perhaps tragic
to conclude that the response of animals to a particular virus infection is the
same as the response of the human to the same virus.
The original association between in utero rubella infection and congenital
abnormalities was made either retrospectively or by examining fetal tissue from
spontaneous abortions. Only the accidental vaccination of pregnant women or
intentional vaccination of pregnant women about to undergo planned abortions fall
into the area that is considered "research on living human fetuses." However,
without these latter studies, the risk to the fetus attendant to vaccination of
the pregnant woman would not have been recognized.
Future Outlook
With regard to the future of rubella vaccination as an effort to prevent
the congenital rubella syndrome, there are several areas of concern which need
to be addressed. These areas of concern clearly dictate what needs to be done
if further research is permitted.
15-15
(1) Because pharyngeal shedding of the vaccine virus occurs,
is there a risk to the fetus if unvaccinated pregnant
women become infected from a vaccinated child?
(2) Although spread of virus by this route may be uncommon,
the relationship between a mother and her young vacci-
nated child may present a unique epidemiological setting.
(3) Although vaccinated children with high levels of antibody
are resistant to clinical evidence of rubella infection
when challenged with wild-type virus, virologic evidence
of reinfection is clear from isolation of challenge virus
in pharyngeal secretions.
The question, therefore, is what is the threat to pregnant women upon
contact with an asymptomatically reinfected child? In addition, are there other
criteria of immunity that would be more useful in predicting susceptibility to
reinfection following immunization?
It was thought from epidemiologic studies that the risk of rubella embry-
opathy is essentially confined to infants whose mothers have suffered clinically
manifest rubella during pregnancy . 3i' 32, 49, 53 jt is reasoned, therefore, that
because vaccine-induced antibodies have reliably prevented clinical rubella after
natural or artificial challenge, the fetus of a mother, whose rubella immunity is
vaccine induced, would be protected, even if the mother were infected during preg-
nancy. However, recent evidence suggests that subclinical infection of the preg-
nant female with rubella virus can also result in congenital abnormalities.
The uniqueness of the rubella vaccine lies in its purpose; not to protect
the recipient from disease, but rather to protect a hypothetical fetus, which
may not be conceived for many years after vaccination, from infection and defor-
mity. To this end, there has been no test of its effectiveness in accomplishing
its purpose — the prevention of embryopathy. This question could be addressed by
studies on women who, for a variety of reasons, would have their pregnancies
voluntarily terminated. If further research were permitted, effects of virus
challenge could then be evaluated on the aborted fetus.
Therefore, the use of rubella vaccine could be very effective, and its
future bright, in preventing the congenital rubella syndrome. However, before
its usefulness can be assessed with any degree of reliability, the above men-
tioned points need to be clarified. The only way to clarify these points is to
study the human fetus. If further human fetal research is permitted, progress
can then be made to determine if the rubella vaccine can accomplish its stated
purpose — to prevent virus-induced embryopathies.
REFERENCES
1. Alford, C.A. , Jr., Neva, F.A. , et al., "Virologic and Serologic Studies on
Human Products of Conception After Maternal Rubella," New Eng. J. Med.
271:1275, 1964.
2. American Academy of Pediatrics, Report of the Committee on Infectious
Diseases, ed. 17, Evanston, Illinois, AAP, 1974.
3. Bolognese, R.J. and Carson, S.L., "Rubella Vaccination: A Critical Review,"
Obstet. Gynecol. 42:851, 1973.
4. Bolognese, R.J., Carson, S.L., et al., "Rubella Vaccination During Pregnancy,"
Am. J. Obstet. Gynec. 112:903, 1972.
5. Brown, G.C. , Maassab, H.F., et al . , "Rubella Antibodies in Human Serum:
Detection by the Indirect Fluorescent-Antibody Technic," Science 145:943,
1964.
6. Carruthers, D.G., "Congenital Deaf Mutism as Sequelae of Riibella-Like Maternal
Infections During Pregnancy," Med. J. Aust. 1:315, 1945.
7. Center for Disease Control, "CDC Standard Rubella Hemagglutination-Inhibition
Test," U.S. Department of Health, Education, and Welfare, Pi±ilic Health
Service, Center for Disease Control, Atlanta, Ga. , 1970.
8. Center for Disease Control, "Proceedings of the Eighth Annual Immunization
Conference," Kansas City, Missouri and Atlanta, Georgia, The Centfer, 1, 1971.
9. Chess, S., Korn, S.T., et al. , "Psychiatric Disorders of Children with
Congenital Rubella," p. 147, Pub. Brunner/Mazel , Inc., 1971.
10. Cooper, L.Z., Matters, B. , et al., "Experience With a Modified Rubella
Hemagglutination-Inhibition Antibody Test," J. Amer . Med. Ass. 207:89, 1969.
11. Cotlier, E. and Fox, J., "Rubella Virus, Cataracts, and the Congenital Rubella
Syndrome," in B. Becker and C.R. Drews (eds.) Current Concepts in
Opthalmology , St. Louis: Mosby, 1967.
12. de Bergen, cited by Wesselhoeft, C. , "Ri±)ella (German Measles)," New Eng. J.
Med. 236:943, 1947.
13. Deibel, R.S., Cohen, M. , et al., "Serology of Rubella: Virus Neutralization,
Immunofluorescence in BHK-21 Cells, and Hemagglutination Inhibition,"
N.Y. State J. Med. 68:1355, 1968.
14. Delahunt, C.S. and Rieser, N., "Rubella-Induced Embryopathies in Monkeys,"
Am. J. Obstet. Gynec. 99:580, 1967.
REFERENCES (Continued)
15. Desmond, M.M. , Wilson, G.S., et al., "Congenital Rubella Encephalitis.
Course and Early Sequelae," J. Pediat. 71:311, 1967.
16. Dogramaci, I. and Green, H., J. Pediat. 30:295, 1947.
17. Ebbin, A.J., Wilson, M.G. , et al . , "Inadvertent Rubella Immunization in
Pregnancy," Am, J. Obstet. Gynec. 117:505, 1973.
18. Field, A.M., Vandervelde, E.M., et al., "A Comparison of the Hemaggluti-
nation-Inhibition Test and the Neutralization Test for the Detection of
Rubella Antibody," Lancet 2:182, 1967.
19. Gregg, N.M., "Congenital Cataract Following German Measles in the Mother,"
Trans. Ophthal . Soc . Aust. 3:35, 1941.
20. Hambridge, K.M., Shaffer, D. , et al., "Congenital Rubella: Report of Two
Cases with Generalized Infection," Brit. Med. J. 1:650, 1966.
21. Hancock, M.P., Huntley, C.C. , et al., "Congenital Rubella Syndrome With
Immunoglobulin Disorder," J. Pediat. 72:636, 1968.
22. Herrmann, K.L., Halonen, P.E., et al., "Evaluation of Serological Techniques
for Titration of Rubella Antibody," Amer. J. Pub. Health 59:296, 1969.
23. Kamberbeek, A.E.H.M. , "HET Rubella Problem in het licht van Nederlandse
Ervaringen," Verhandl van hit Instituuit por praeventieve Geneskunde 14
Leiden., 1949.
24. Karmody, C.S., "Subclinical Maternal Rubella and Congenital Deafness,"
New Eng. J. Med. 278:809, 1968.
25. Katz, M. , "Rubella Vaccine," J. Pediatr. 84:615, 1974.
26. Klock, L.E. and Rachelefsky, G.S., "Failure of Herd Immunity During an
Epidemic," N. Eng. J. Med. 288:69, 1973.
27. Korones, S.B., Ainger, L.E., et al., "Congenital Rubella Syndrome: New
Clinical Aspects with Recovery of Virus from Affected Infants," J. Pediat.
67:166, 1965.
28. Larson, H.E., Parkman , P.D. , et al., "Inadvertent Rubella Virus Vaccination
During Pregnancy," N. Eng. J. Med. 284:870, 1971.
29. Lennette, E.H. , Schmidt, N. J. , et al., "The Hemagglutination-Inhibition Test
for Rubella: A Comparison of Its Sensitivity to that of Neutralization,
Complement Fixation, and Fluorescent Antibody Tests for Diagnosis of
Infection and Determination of Immunity Status," J. Immunol. 99:785, 1967.
15-18
REFERENCES (Continued)
30. Lindsay, J.R. and Harrison, R.S., "The Pathology of Rubella Deafness,"
J. Laryngol. Otolaryngol. 68:461, 1954.
31. Lundstrom, T.C. and Bloomquist, B. , "Gamma Globulin Against Rubella in
Pregnancy. I. Prevention of Maternal Rubella by Gamma Globulin and
Convalescent Serum Globulin: A Follow-Up Study," Acta Pediat. 50:444,
1961.
32. McDonald, J.C., "Gamma-Globulin for Prevention of Rubella in Pregnancy,"
Brit. Med. J. 2:416, 1963.
33. Menser, M. , Dods , L., et al . , "A Twenty-Five-Year Follow-Up of Congenital
Rubella," Lancet ii:1347, 1967a.
34. Meyer, H.M., Parkman, P.O., et al., "Attenuated Rubella Virus. II. Production
of an Experimental Live-Virus Vaccine and Clinical Trial," N. Eng . J. Med.
275:575, 1966.
35. Monif, G.R.G., Sever, J.L., et al., "Isolation of Rubella Virus from Products
of Conception," Am. J. Obstet . Gynec. 91:1143, 1965.
36. Murphy, A.M., et al., "Rubella Cataracts: Further Clinical and Virologic
Observations," Am. J. Opthal . 64:1109, 1967.
37. Mutrux, S. , Wildi, E. , et al . , "Contribution a 1' etude clinique et anatomo-
pathologique des troubles cerebraus de 1 'embryopathie rubeoluse," flrch.
Neurol. Psychiat. 64:369, 1949.
38. Parkman, P.D., Buescher, R.L., et al., "Recovery of Rubella Virus from Army
Recruits," Proc. Soc. Exp. Biol. Med. 111:225, 1962.
39. Parkman, P.D., Meyer, H.M. , et al., "Attenuated Rubella Virus. I. Development
and Laboratory Characterization," N. Eng. J. Med. 275:569, 1966.
40. Parkman, P.D., Mundon, F.K. , et al . , "Studies of Rubella. II. Neutralization
of the Virus," J. Immunol. 93:608, 1964.
41. Parkman, P.D., Phillips, P.E., et al., "Experimental Rubella Virus Infection
in Pregnant Monkeys," Am. J. Dis . Child. 110:390, 1965.
42. Phillips, C.A. , Maeck, J.V.S., et al., "Intrauterine Infection Following
Immunization with R\±>ella Vaccine," JAMA 213:624, 1970.
43. Plotkin, S.A., Boue , A., et al . , "The In Vitro Growth of Rubella Virus in
Human Embryo Cells," Am. J. Epidemiol. 81:71, 1965.
44. Public Health Service Advisory Committee on Immunization Practices. Collected
Recommendations, Morbidity and Mortality Weekly, Report 21 (Suppl. 25),
1, 1972.
REFERENCES (Continued)
45. Rawls, W.E. and Melnick, J.L., "Rubella Virus Carrier Cultures Derived from
Congenitally Infected Infants," J. Exp. Med. 123:795, 1966.
46. Raid, R.R., et al., "Isolation of Riibella Virus from Congenital Cataracts
Removed at Operation," Med. J. Aust. 1:540, 1966.
47. Rorke, L.B., "Nervous System Lesions in Congenital Rubella Syndrome,"
Arch. Otolaryngol. 98:249, 1973.
48. Rudolph, A.J., Singleton, E.B., et al., "Osseous Manifestations of the
Congenital Rubella Syndrome," Am. J. Dis . Child. 110:428, 1965.
49. Schiff, G.M. and Sever, J.L., "Rubella: Recent Laboratory and Clinical
Advances," Prog. Med. Virol. 8:30, 1966.
50. Selzer, G. , "Virus Isolation, Inclusion Bodies, and Chromosomes in a Rubella-
Infected Human Embryo," Lancet 2:336, 1963.
51. Sever, J.L., Fuccillo, D.A. , et al . , "Rubella Antibody Determinations,"
Pediatrics 40:789, 1967.
52. Sever, J.L., Huebner, R.J., et al., "Rubella Complement Fixation Test,"
Science 148:385, 1965.
53. Sever, J.L., Nelson, K.B., et al . , "Rubella Epidemic, 1964 Effect on 6000
Pregnancies," Am J. Dis. Child. 110:395, 1965.
54. Stewart, G.L., Parkman, P.D., et al., "Rubella-Virus Hemagglutination-
Inhibition Test," N. Eng. J. Med. 276:554, 1967.
55. Singer, D.B., Rudolph, A.J., et al . , "Pathology of the Congenital Rubella
Syndrome," J. Pediat . 71:665, 1967.
56. Swan, C, et al . , "Congenital Defects in Infants Following Infectious
Disease During Pregnancy, with Special Reference to Relationship Between
German Measles and Cataracts, Deaf-Mutism, Heart Disease, and Microcephaly,
and to Period of Pregnancy in Which Occurrence of Rubella is Followed by
Congenital Abnormalities," Med. J. Aust. 2:201, 1943.
57. Tondury, G. , "Pathologie und Klinik in Eindeldarstellungen: XI Embryo-
pathien," Berlin, Springer-Verlag, 1962.
58. Tondury, G. and Smith, D.W. , "Fetal Rubella Pathology," J. Pediat. 68:867,
1966.
59. Vaheri, A., Vesikari, T. , et al., "Transmission of Attenuated Riobella Vaccines
to the Human Fetus," Am. J. Dis. Child. 118:243, 1969.
15-20
REFERENCES (Continued)
60. Veale, H. , "History of an Epidemic of Rotheln, With Observations on Its
Pathology," Edin. Med. J. 12:404, 1866.
61. Waller, T.H. and Neva, F.A., "Propagation in Tissue Culture of Cytopathic
Agents from Patients with Rubella-Like Illness," Proc. Soc . Exp. Biol.
Med. 111:215, 1962.
62. Witte, J.J., Karchmer, A.W. , et al., "Epidemiology of Rubella," Am. J. Dis.
Child. 118:107, 1969.
Principals Interviewed
Dr. Tom Weller
Boston Children's Hospital
Department of Pediatrics
Boston, Massachusetts
Dr. Oxman
Boston Children's Hospital
Department of Pediatrics
Boston, Massachusetts
to
oc
o
< t cc
I- ;j w
y CD _J
u. 3 -I
Z u. 3
^•o <
oc z
oo
UJ
3
H
tu
II
lU
X
1-
o
<o
z »
<
Z
o<
(A
Ui
o
Z
o
UJ
z
z
Z
<
3
X
O
z
>
a
z
o
D
_J
o
z
VING N
ANEOUS
PSY)
-1
<
z
8
<
<
D
NONLI
SPONT
(AUTO
I
X
-1
—
<
u.
2
X
X
X
u
Z
<
O _j
U. UJ
w a*
Q D
OOC
SZ
-.9
< K
O <
o t
oc 111
Hi Q
V) —
^-d
I
OQ
D
X
<
-1
-I
u.
UJ
O
OQ
z
rr
o
1-
<
<
H
N
z
X
III
UJ
1-
z
o
UI
<
o
X
X
n
<
u
z
T Z
V
o<
M
S3
<iX >
I L
Si s;
J I L
iS2£Z
J I
§^2
_i o
< Ui
t 5
CHARACTERIZATION OF RUBELLA
AND CONGENITAL RUBELLA
SYNDROME
ISOLATION, IDENTIFICATION, AND
ASSOCIATION OF RUBELLA WITH
CONGENITAL RUBELLA SYNDROME (CRS)
DETECTION
er<DEMIC
AUSTRALIAN
Iia34-1M0I
) AS DISEASE ENTIl
NEONATES
HN
HN
HN
— SWANN. 1943
— KAMERBEEK. 1949
PROGRESSIVE DEAFNESS IN NEONATE (RUBELLA)
N/HN
. BONE STUDIES
> TONOURY. 1962
CATARACTS ANO
HN/H
CODES
HN HUMAN NEONATE
H HUMAN
LHF LIVING HUMAN FETUS
(INCLUDING MOTHER)
N NONLIVING NEONATE OR
SPONTANEOUS ABORTION
(AUTOPSY)
A ANIMAL
SYNDROME DESCRlE
HN/H/N
SCOPE AND VARIETY Of CONGENH
THAN FIRST THOUGHT
HN/H
HN/H
HYPERTENSION
'"" HN/H
ISOLATIC
J AMMiON CULTURES
*SSAY IN AFRICAN GREEN H/A
FROM FETAL TISSUE t
N/HN
LHF/N/HN
) FROM VAHIOUS N/HN
HN/H
SOURCES OF
PURPOSEf UL INOCULATION C
OF HN
NT LHF
OF PREGNANT ■ |ju
r ISOLATION unr-
SEROLOGICAL METHODS FOR
IDENTIFICATION OF RUBELLA
n* PARKMAN, 1963; WELLER, 1983; NEVA. ISO
RUBELLA VIRUS WAS ISOLATED IN CELL CULTURE
H
r{:
• BROWN, 1964
ANTIBODIES TO
BE DETECTED G
lELLA VIRUS COULD
NCE TEST
\ complement-f
1 detection of f
; LENNETTE. 1«7; SEVER, 19fl7
IDtPENDENT INVESTIGATORS CON-
RESULT THE HEMAGGLU
HEMAGGLUTiNATIC
rdizing The
k STANDARD
RUBE
lLA VACCINE DEVELOPMENT
~ fmsfbu^CAL VACCINE TRIALS H/A
,972 LHF
DEVELOPMENT
LHF
■
■
SUBSEQUENT VACCINE
"sTUDIEr^""' ''" H
^^^MMERCI.LPROOUCTION
"3:k
— USPMS. 1971
FAILURE OF '-
TV PROGRAM H
. PHILLIPS. 19T0; LARSON, t
ACCIDENTAL VACCINATIO
FEMALES WITH SUBSEOUE
,ERDI««UN
TY H
Figure 1. Historiograph — Congenital Rubella Syndrone
AMNIOCENTESIS
Medical Significance
Amniocentesis may be defined as a technique for obtaining amniotic fluid
by inserting a needle into the amniotic cavity. This technique may be performed
in the early second trimester for purposes of detecting genetic defects; for
purposes of removing amniotic fluid, subsequently followed by the injection of
an abortifacient for midtrimester abortion; or in the third trimester for the
detection of hemolytic disease, fetal distress, or fetal maturity.
The intrauterine diagnosis of amniotic fluid and cells is assuming
increasing importance in the management of developmental, metabolic, and cyto-
genetic defects in the fetus because fetal abnormality represents an important
cause of perinatal mortality and morbidity. The primary indications for using
amniocentesis can be categorized into fetal and maternal^^^ as shown by the fol-
lowing outline.
A. Fetal indications for amniocentesis
1. Sex-linked disease
2. Chromosomal abnormalities
3. Inborn errors of metabolism -- . --
4. Rh isoimmunization
5. Fetal maturity determination
6. Fetal distress. ■
B. Maternal indications for amniocentesis
1. Polyhydramnios
2 . Abortion
a. Therapeutic - - -.
b. Elective.
Each of the above indications will be described below.
Because amniocentesis is a surgical procedure, the procedure itself, its
timing and possible complications are of great importance. Accordingly, such
information has been included as an appendix to this report. Also included in
the appendix is a discussion of amniography, ultrasonography, amnioscopy, and
fetoscopy which are adjuncts to or outgrowths of amniocentesis.
15-25
Fetal Indications for Amniocentesis
1. Sex-Linked Disease. It has been shown that the cells in the amniotic
fluid, unless contaminated by maternal blood, are of fetal origin.*'-^* These
fetal cells can be examined to determine the sex of the fetus, which is of major
importance if the familial history indicates that the pregnancy involves the
possibility of a sex-linked genetic disorder through familial history. Sex
determination is useful in genetic disorders because the disorder is associated
with the recessive gene located on the human X-chromosome. The more common
X-linked diseases are shown in Table 1.
Table 1. Common X-Linked Disorders
1.
Hemophilia
2.
Duchenne's Muscular Dystrophy
3.
Nephrogenic Diabetes Insipidus
4.
Hunter's Syndrome
5.
Lesch-Nyhan Syndrome
6.
Fabry 'e Disease
Of these X-linked disorders, only the Lesch-Nyhan syndrome. Hunter's
syndrome, and Fabry's disease can be diagnosed in utero via amniocentesis.
Since the mutant gene for the sex-linked disease is carried on one of the X-
chromosomes of the female, transmission of the recessive X-linked disease is
from a female carrier to an affected male. Thus, a woman carrier transmits
the mutant gene to half of their daughters (also carriers) and to half of their
sons, who will be affected. 84 as a result of these recessive sex-linked dis-
eases and their manifestations, the diseases are confined almost exclusively
to the male population. Amniocentesis serves a very important need in the
detection of these male fetuses, who are being carried in suspected women car-
riers, because they have a 50 percent risk of being affected.^^
2. Chromosomal Abnormalities. Numerically, the major indication for
amniocentesis in the second trimester of pregnancy is to identify chromosomal
anomalies. The more common chromosomal anomalies which can be detected by
amniotic fluid cell cultures and karyotyping are identified in Table 2.
Chromosomal anomalies can reflect either an absence of chromosomal mate-
rial (Turner's syndrome) or an excess as shown by the other abnormalities. In
trisomies, one of the explanations for a chromosomal gain is nondisjunction, or
15-26
a failure of the gamete to split equally during the meiotic division. However,
if nondisjunction occurs during mitosis and after fertilization, the result is
an individual with cells of two or more different chromosomal constituents,
i.e., a chromosomal mosaic. ^^
Table 2. Chromosomal Aberrations Detectable by Amniotic
Fluid Cell Culture and Karyotyping 5"
1.
Down ' s Syndrome
Trisomy 21
Translocation D/G
2.
Turner's Syndrome (XO)
3.
Klinefelter 's Syndrome (XXY)
4.
Trisomy 18 (E group) or Edward's Syndrome
5.
Trisomy 13-15 (D group) or Pataus ' Syndrome
6.
Cri du chat Syndrome 46 (Bp)
7.
XXX females
8.
XYY males
Significant chromosomal abnormalities have been estimated to occur about
once in every 200 live births. Over 700,000 infants with such abnormalities
are being born each year worldwide. Of this number, 20,000 such infants are
born in the United States alone. ^'^ The most frequently encountered chromosomal
aberration is mongolism (Down's syndrome), with the incidence of this abnormal-
ity dependent upon the age of the mother. With such a large number of infants
being born each year with a chromosomal abnormality, the use of amniocentesis
to diagnose these abnormalities in utero , especially in high risk patients, is
becoming an accepted clinical practice.
3. Inborn Errors of Metabolism. The metabolic diseases (inborn errors
of metabolism) may be diagnosed from amniotic fluid, cultured amniotic fluid
cells, or uncultured amniotic fluid cells. As Milunsky points out,*'' "Progress
has basically occurred in a stepwise fashion from the study of disorders in vivo
to the delineation of specific abnormalities in tissues, to the recognition of
these abnormalities in cultured skin fibroblasts, leukocytes, and finally cul-
tured amniotic fluid cells."
15-27
Critical to the prenatal diagnosis of these metabolic diseases is the
assumption that cultured skin fibroblasts or amniotic fluid cells will continue
to demonstrate the specific characteristics of that disease throughout succes-
sive cultures. This is critical because the metabolic diseases are usually
identified by a particular deficient or reduced enzyme activity or by a spe-
cific accumulating storage substance. The assumption that cultured amniotic
fluid cells do retain their enzymatic activity through successive cultures
appears to be valid. Thus, the metabolic disorders identified to date, involving
either amniotic fluid, cultured amniotic fluid cells or noncultured amniotic
fluid cells, number 16 with the possibility of identifying 15 more.^* These are
given in Tables 3 and 4. A more recent estimate suggests more than 40 biochem-
ical disorders can now be diagnosed in utero.'*
Table 3. Metabolic Disorders Diagnosed Prenatally To Date'
Disorder
Diagnosis
Made From
1.
Disorders of Lipid Metabolism
(a)
Cm, gangliosidosis (Tay-Sachs)
Noncultured amniotic fl
aid cells
Cultured
amniotic
fluid
cells
Amniotic
fluid
(b)
Metachromatic leukodystrophy
Cultured
amniotic
fluid
cells
(c)
Krabb's disease
Cultured
amniotic
fluid
cells
(d)
Niemann-Pick disease, Type A
Cultured
amniotic
fluid
cells
(e)
Gaucher 's disease
Cultured
amniotic
fluid
cells
(f)
Fabry's disease
Cultured
amniotic
fluid
cells
2.
Mucopolysaccharidosis
(a)
Hurler ' s syndrome
Cultured
Amniotic
amniotic
fluid
fluid
cells
3.
Aminoacid Disorders
(a)
Maple syrup urine disease
Cultured
amniotic
fluid
cells
(b)
Methyl malonic aciduria
Amniotic
fluid
4.
Disorders of Carbohydrate Metabolism
(a)
Glycogen storage disease Type II
(Pompe's disease)
Cultured
Amniotic
amniotic
fluid
fluid
cells
(b)
Galactosemia
Cultured
amniotic
fluid
cells
5.
Miscellaneous
(a)
Adrenogenital syndrome
Amniotic
fluid
(b)
Lesch-Nyhan syndrome
Cultured
amniotic
fluid
cells
(c)
Lysosomal acid phosphatase
deficiency
Cultured
amniotic
fluid
cells
(d)
Cystic fibrosis
Cultured
amniotic
fluid
cells
(e)
Marfan 's syndrome
Cultured
amniotic
fluid
cells
15-28
Table 4. Metabolic Disorders in Which Prenatal
Diagnosis Should be Possible ^*
Disorder
Enzyme Located
In
1.
Disorders of Lipid Metabolism
(a) Gm-j^ ganliosidosis
Cultured
amniotic
fluid
cells
(b) Ref sum's disease
Amniotic
fluid
Cultured
amniotic
fluid
cells
2.
Mucopolysaccharidosis
(a) Hunter's syndrome
Cultured
Amniotic
amniotic
fluid
fluid
cells
3.
Aminoacid Disorders
(a) Arginosuccinic aciduria
Cultured
amniotic
fluid
cells
(b) Cystinosis
Cultured
amniotic
fluid
cells
(c) Homocystinuria
Cultured
amniotic
fluid
cells
(d) Hyperaimnonemia , Type II
Noncultured amniotic fluid cells
(e) Ornithine-a-ketoacid trans-
aminase deficiency
Cultured
amniotic
fluid
cells
4.
Disorders of Carbohydrate Metabolism
(a) Fucosidosis
Cultured
amniotic
fluid
cells
(b) Glycogen storage disease,
Type III
Cultured
amniotic
fluid
cells
(c) Glycogen storage disease,
Type IV
Cultured
amniotic
fluid
cells
(d) Mannosidosis
Cultured
amniotic
fluid
cells
(e) G6PD deficiency
Noncultured amniotic fluid cells
5.
Miscellaneous
(a) Orotic aciduria
Amniotic
fluid
(b) Xeroderma pigmentosum
Cultured
amniotic
fluid
cells
Although each one of these metabolic diseases is relatively rare in the
general population, some inherited disorders of metabolism may occur with an
estimated frequency as high as one in 100 live births.^* In addition, once there
is an affected individual in a particular family, the condition becomes preva-
lent in that family because most of the inborn errors of metabolism are inherited
as autosomal recessives and the risk of an affected offspring is, therefore, one
in four in a given sibship. Thus, if both parents were carriers of a specific
inborn error of metabolism, the fetus could be monitored via amniocentesis.
Eventually, in some of the inborn errors of metabolism, therapy for the fetus
might be theoretically possible, either directly or via the mother.
15-29
4. Rh Isoimmunization. Ever since the demonstration of the relationship
between pigment content of the amniotic fluid and the severity of hemolytic dis-
ease of the newborn, amniotic fluid analysis has become a standard procedure in
the management of the rhesus sensitized pregnant woman .^s There is little argu-
ment that this observation popularized amniocentesis in the United States .i^*
However, with the development of Rh vaccine, hemolytic disease in the newborn
is now almost totally limited to Rh-negative women who were sensitized prior to
the availability of Rh vaccine and to the small percentage (2 or 3 percent) of
Rh-negative women who become sensitized without apparent cause .^^
Maternal isoimmunization presents a varied pathologic and clinical mani-
festation of the hemolytic disease syndrome in either the fetus or newborn.
When maternal antibodies (Rh-positive) gain access to the fetal circulation,
they are adsorbed upon the Rh-negative erythrocyte. These adsorbed antibodies
act as hemolysins which cause the breakdown of the fetal red blood cells with
the resultant erythroblastotic fetus.
With the discovery that the height of the spectrophotometric peak at
450 my (corresponding to unconjugated bilirubin) correlated well with the sever-
ity of the fetal hemolytic condition, it became possible to treat the erythro-
blastotic fetus via intrauterine blood transfusions. Because the intrauterine
determination of the fetal blood groups is possible, it is now possible to match
the fetus's blood group with the planned intrauterine blood transfusion.
A recent advance in regard to intrauterine transfusions has been the
association of the estriol concentration in amniotic fluid with fetal well-being.
It has been demonstrated that an increase in amniotic fluid estriol levels cor-
relates well with increased fetal survival. In conclusion, the role of amnio-
centesis in the past treatment of erythroblastosis fetalis is apparent, but the
value of the technique in this instance should be decreasing with the advent of
the vaccine.
5. Fetal Maturity Determination. Another indication for amniocentesis
is to determine the gestational age, since there are conditions where it is
desirable to terminate the pregnancy prematurely to assure the viability of
that fetus. The determination of gestational age would be warranted in a dia-
betic pregnancy, in erythroblastosis fetalis, in severe preeclampsia, or in a
prolonged pregnancy ."^
Other methods such as examining the external uterus, ultrasonography,
fetal electrocardiograms, placental biopsies, measurements of the urinary
estriol excretion, amniography, fetal encephalography, and auscultation of the
fetal heart have not always provided the desired information about the fetus .^^
As a result, recent attention has been directed toward the amniotic fluid for
providing an indication of fetal maturity. The four principal methods which
have been used to date include:
(1) The spectrophotometric analysis of amniotic fluid for
bilirubin
(2) The measurement of amniotic fluid creatinine
(3) The detection and staining of exfoliated fetal cells
from amniotic fluid
(4) The lecithin/sphingomyelin ratio in amniotic fluid.
The association of fetal maturity and the disappearance of bilirubin in
unsensitized pregnancies was noted by Mandelbaimi et al.'*'^' They observed
a precipitous decline and disappearance of the absorbance bulge at 450 my at
36 to 38 weeks' gestation. The second method, involving creatinine determina-
tion in the amniotic fluid, has shown that with increasing fetal age, there is
also an increase in the amniotic fluid creatinine. The concentration of creat-
inine remains almost constant or gradually increases from 32 to 36 weeks, after
which there is a more marked increase. Thus, in contrast to creatinine, the
bilirubin concentration is highest in midtrimester and thereafter decreases in
a linear manner until it virtually disappears at 35 or 37 weeks. ^9 Recently,
Foulds and Pennock-'^ have shown that the creatinine method is probably unreliable
for estimating fetal maturity in clinical practice.
A third method for determining fetal maturity is to stain the exfoliated
cells obtained in amniotic fluid. The lipid-containing cells of the amniotic
fluid, upon staining with Nile blue sulfate, are seen as orange-colored cells.
The concentration of these cells usually increases markedly after 36 weeks
gestation, and the presence of greater than 50 percent of the cells stained
orange usually indicates the gestation is at term.'*
A fourth method for determining fetal maturity involves determining the
lecithin/sphingomyelin ratio in amniotic fluid. This ratio is of importance in
defining the fetus's pulmonary maturity since a frequent consequence of premature
birth is the respiratory distress syndrome. In 1971, Gluck et al.,^i suggested
that surface-active phospholipids may come from the fetal lung. In addition, he
suggested that there are two metabolic pathways for lecithin production and that
the more mature and stable pathway becomes dominant about the thirty-fourth to
thirty-fifth week. This pathway is associated with an increase in the amount of
lecithin in relation to sphingomyelin found in the amniotic fluid. Thus, if the
lecithin/sphingomyelin ratio is 2.0 or greater prior to delivery, it is rare to
have a neonate die from hyaline membrane disease. On the other hand, if the level
is below 1.5, there is a 50 percent chance (without special neonatal care) that
the neonate will die from hyaline membrane disease, since the incidence of hyaline
membrane disease decreases markedly after 34 to 35 weeks' gestation. ^2
6. Fetal Distress. For many years, the presence of meconium in the
amniotic fluid was associated with fetal distress. However, transabdominal
amniocentesis for the detection of meconium staining of the amniotic fluid did
not become popular until 1962.65 Even then there was limited use of meconium
staining as an indicator of fetal distress because the mechanism provoking the
release of meconium by the fetus was not fully understood. Thus, a meconium-
stained amniotic fluid is not a very accurate diagnostic procedure prior to
labor but can be a reliable screening method for higher risk cases. ss
In 1962, Salingio-' introduced the technique of amnioscopy. Its value was
in observing the amniotic fluid directly for meconium staining in certain
15-31
high-risk pregnancies. Thus, compared to amniocentesis, it was more convenient
to use but it suffered from the disadvantage of inability to assess the color
as accurately as via amniocentesis. The yellow color of bilirubin is very
obvious , but the color may be confused with hemoglobin so that spectrophoto-
metric analysis must be the basis of clinical judgment. ""^
Maternal Indications for Amniocentesis
The maternal indications for amniocentesis are polyhydramnios ^^ and either
a therapeutic or elective abortion. Polyhydramnios refers to the excessive
accumulation of fluid in the amniotic cavity. At term, the normal volume of
amniotic fluid is 1.0 to 2.0 liters. However, in polyhydramnios, the volume of
fluid is greater than 2.0 liters and is often excessive. More importantly, the
incidence of fetal malformations, especially those of the central nervous system
and gastrointestinal tract, are extremely high when polyhydramnios is present.
There is no satisfactory treatment for polyhydramnios other than removal of the
excess fluid. This can be accomplished via abdominal amniocentesis and the
main objective is to relieve the patient's distress or to avoid the uterine
dysfunction which usually accompanies labor in the presence of hydramnios .^s
However, withdrawal of fluid via amniocentesis may lead to premature labor.
Although amniocentesis as a procedure is usually thought of in terms of
removing amniotic fluid, there are situations in which fluid is instilled
directly into the amniotic cavity, either for diagnostic (amniography) or thera-
peutic purposes. This might be the case when an abortion is considered. In the
former case, amniocentesis might be performed twice, once to diagnose a suspect
genetic disease and again to withdraw large amounts of amniotic fluid that is
subsequently replaced by an abortif acient to induce an abortion. ^^ In the latter
case, no prior amniocentesis need be performed, but the procedure itself is iden-
tical to that described for a therapeutic abortion.
As can be seen from the above, there are many indications for using amnio-
centesis in prenatal care, either as a diagnostic aid or for carrying out a
therapeutic procedure. The risks and complications associated with amniocentesis
are relatively rare (the current work estimate is 1 to 2 percent) , but these
risks and complications must be weighed against the indications for using the
procedure .
An indirectly associated parameter which also must be evaluated in employing
amniocentesis is the accuracy of the diagnostic technique being performed. The
diagnostic accuracy of a test can be affected by the cell origin, cell growth
in culture, or the culture medium. 81,102.106
Difficulties can be encountered in the utilization of amniotic fluid
per se. These difficulties include (1) the possibility of maternal blood admix-
ture which could lead to errors in the interpretation of many different enzyme
analyses, (2) the amniotic fluid may become contaminated with bacteria, (3) vari-
ations in amniotic fluid cell number and viability, especially the uncultured
cells, may lead to an unreliable diagnostic test, (4) changing protein content
in the amniotic fluid with gestational age makes a biochemical analysis diffi-
cult if it requires expression per milligram of protein, and (5) the unknown
quantity and quality of fetal urine in early gestation further complicates the
use of amniotic fluid alone in making a prenatal diagnosis .^^
Some of the more common difficulties encountered in working with cells
from amniotic fluid are as follows: (1) at different stages of gestation, the
cells may show enzyme activity changes; (2) cultured cells divide every 16 to
30 hours, in contrast to the generation time of 30 to 90 days in the living
organism; (3) cyclical changes in enzyme activity have been observed; (4) meta-
bolic activity of the cells may be profoundly affected during the initial
establishment of a culture, since there is a lag phase in establishing a cul-
ture; (5) long periods of time may be required to grow sufficient amniotic
fluid cells; (5) the culture medium and serum used to grow the cells may effect
the cellular enzyme activity; and (7) since trypsin remains the most effective
agent for cell dissociation aimed at primary isolation or passage of cells in
vitro, the toxic effects of trypsin must be taken into account. s^
It would appear that even with all these factors which might affect the
accuracy of the prenatal diagnosis, the accuracy of diagnosing a particular
genetic defect has been relatively high, i.e., greater than 90 percent. ^9 In
another study, only ten errors were made in a total of 1,533 cases studied.^*
Of these ten errors, the fetal sex was inaccurately diagnosed in seven cases,
but none of these cases involved X-linked diseases. However, fetal sex deter-
mination is now almost 100 percent diagnosable with the advent of the fluores-
cent acridine derivative for staining chromosomes which now complements the
Barr-body technique .
An Example of the Impact of Amniocentesis In Diagnosing a Significant
Congenital Disorder
Although there are minimal risks and complications associated with amnio-
centesis, as pointed out in an earlier section, the impact of amniocentesis as
a diagnostic aid in the management of congenital disorders is significant.
Of the known chromosomal aberrations, the most frequently encountered is
Down's syndrome or mongolism. This abnormality has an especially high risk with
advancing maternal age. Bodensteiner and Zellweger i* performed a study on mon-
golism in 1971 in which they calculated the incidence of mongolism for the
state of Iowa (approximately 3 million population with 50,000 live births/year).
In their study, five groups of women were identified with a high risk for
mongolism (Table 6) .
Table 6.
Groups of Women Identified as Possessing
A High Risk for Down's Syndrome'*
1. VJomen 40 years of age and over
2. Women 35-40 years of age with a previous mongoloid child
3 . Mongoloid women
4. Parental mosaicism with a 21 trisomic cell population
5. Familial translocation (G/G and D/G)
15-33
Of the above five groups, only the first two contribute significantly to
the incidence of mongolism. In the first group (women 40 years of age and over) ,
they found that about 2 percent of the children born would be mongoloid. In
this group there was an average of 1000 births per year (with a defect incidence
rate of 1 per 50 live births) , which meant 20 cases of mongolism could be
detected in this group per year.
In the second group, the mongolism incidence of all mothers in the age
group (35-39 years) is approximately 1 per 250 live births. However, if the
mother has given birth previously to a mongoloid child, the incidence increases
to 1 per 80 live births. In the Iowa study, there were approximately 6,000
births out of the total 50,000 live births per year which were born to mothers
in the age group (35-39 years) . Of this total only 40 mothers had previously
given birth to a mongoloid child so that every two years one case of mongolism
could be detected in this group.
There are, however, many practitioners who feel that even mothers 35-39
years old should be considered in the "high risk" group and should not simply
be confined to a mother in this age group who has previously given birth to a
mongoloid child. If one accepts this statement, then in the Iowa study, there
would have been 20 more cases of mongolism detected since the incidence for all
mothers in this age group is 1 per 250 live births.
In summary, Bodensteiner and Zellweger ■''' have shown that according to their
classification, the advance detection of 20 cases of mongolism per year would be
possible via amniocentesis. If group two were expanded to include all mothers
35-39 years of age, a total of about 45 cases of mongolism could be detected.
Extrapolation of the Iowa statistics, which are probably consistent with the
national average, would suggest that approximately 2,880 children with Down's
syndrome could be detected each year (assuming 3.2 million births/year).
It has been estimated that if these defective children were institution-
alized, the cost to society each year would be $17,500,000 ($6100/year/case)^^
while the cost of routinely providing amniocentesis and prenatal genetic studies
to the 448,000 patients which would produce the 2,880 children with Down's syn-
drome would be approximately $57 million. If all positively diagnosed cases
were aborted at a cost of $400 per procedure, the additional cost would be about
$1.2 million. However, if one assumes an average life expectancy for the defec-
tive child of 50 years, the cost of caring for 2,880 individuals over that time
span would be almost $875 million dollars. Thus, each year with the birth of
a similar number of mongoloid children, a future commitment of $875 million per
year is created, versus $68.2 million per year to diagnose all high risk preg-
nancies and abort those positively diagnosed. It should be kept in mind that
these figures are for Down's syndrome only and that there are about 5,100 seri-
ously defective offspring per year based on 3.2 million live births per year.^
15-34
Historical Account
Amniocentesis as a case differs from the others studied here in that it
is a procedure used primarily as a prelude to a diagnostic procedure, whereas
the other cases involved the development of a therapeutic or prophylactic treat-
ment. Comparatively little research in the strictest sense has been done on
amniocentesis as a procedure. In view of this, we have chosen to emphasize the
key ancillary procedures which have been developed and used in conjunction with
amniocentesis and the use and application of the procedure as it relates to
fetal diagnostic tests and therapeutic methods.
Key Ancillary Procedures . ■
In 1882, SchatziO'' introduced the concept of puncturing the amniotic cavity
by the transabdominal route for therapeutic purposes, i.e., the removal of fluid
in polyhydramnios. Thus was born the idea of amniocentesis. The first ancillary
procedure to be used in conjunction with amniocentesis occurred in 1930 when
Menees et al.,^° injected strontium iodide into the amniotic cavity. By employ-
ing amniocentesis, they developed amniography which permitted the visualization
of fetal soft parts and localization of the placenta. They also noted that
amniography could be of value in diagnosing placenta praevia and determining
the exact relation of the placenta to the cervical canal.
Although meconium staining of the amniotic fluid had been known to be a
sign of fetal distress, the use of amniocentesis for the detection of meconium
staining did not become popular until Kubli's work in 1962 .^^ j^ addition to
using amniocentesis for identifying meconium stained amniotic fluid, Saling,i°3
in 1962, introduced amnioscopy. This technique employed an endoscope that
could be introduced through the dilating cervical canal at term. After passage
through the cervical canal, the amniotic fluid could be examined directly
through the intact membranes to demonstrate the presence of meconium and moni-
tor fetal distress. However, it suffered from the major disadvantage that
fluid was not collected via this procedure. Thus, one could not perform bio-
chemical or photometric evaluations on the amniotic fluid.
A recent outgrowth of amnioscopy, fetoscopy — the transabdominal insertion
of an endoscope into the gravid uterus — has been developed. ^^^ This useful
diagnostic tool allows the clinician to visualize the intrauterine contents
and make clinical diagnoses based on the information obtained.
Intrauterine blood transfusions for treatment of fetal hemolytic disease
is an ancillary procedure developed as a consequence of amniocentesis. However,
this topic is discussed under a subsequent section on Rh isoimmunization.
The demonstration by Gottesfeld in 1966^^ that ultrasound could be used
to localize the placenta prior to amniocentesis will probably be one of the key
developments in reducing the risks and complications associated with amniocen-
tesis. In their study, the use of ultrasound correctly predicted the position
of the placenta in 97 percent of the cases.
15-35
Significant Events as Regards Diagnostic Tests and Therapeutic Methods
Rh Isoimmunization. The chronological events which would relate directly
to amniocentesis in diagnosing and treating fetal hemolytic disease was initi-
ated by the discovery of the Rh antigen, so called because it was found origi-
nally on ■ the red cell of the rhesus monkey, by Landsteiner and Weiner.*' In
1940, they reported that the erythrocytes of 85 percent of a group of Caucasians
reacted positively with the antirhesus serum, whereas 15 percent did not. Thus,
the former group contained the antigen and were termed Rh positive while those
that did not, were referred to as Rh negative.
In 1956, Bevis'^ postulated that the severity of hemolytic disease could
be determined by measuring the "blood pigments" present in amniotic fluid.
The specific blood pigments measured were bilirubin and oxyhemoglobin and their
concentration in the amniotic fluid indicated the degree of hemolysis which was
occurring in the fetus.
When Coombs et al.,^' in 1956 introduced a technique for detecting blood
group antigens on epidermal cells, by specific mixed agglutination, they opened
a pathway for the detection of fetal antigens via amniotic fluid cells. That
same year, Fuchs et al.,''8,44 developed a method for the determination of the
fetal ABO blood groups in amniotic fluid. They found that it was possible to
detect A and B antigens in the amniotic fluid cells which were of fetal origin.
In 1957, Walker'^^ expanded on the clinical application of Bevis ' technique
by examining the spectral absorption curves of amniotic fluid in rhesus sensi-
tized patients. He claimed that it was possible to predict which babies were
affected by hemolytic disease provided the amniotic fluid was obtained prior to
the thirty-fifth week. This development led to Liley's findings^^ in 1961, where
he confirmed Bevis' and Walker's techniques, that the spectral absorption curve
of liquor amnii presents diagnostic features in hemolytic disease and shows that
the size and progress of the characteristic peak at 450 my reflects the severity
of anemia. In addition, Liley was able to show that the size and trend with
maturity of the 450 my peak provided an indication of the severity of anemia and
prognosis for the fetus.
The refinement in prognostic precision of pregnancies complicated by rhesus
sensitization led Liley in 1963'° to try the first intrauterine transfusion of
blood into the fetal abdomen.
As a result of the successful intrauterine transfusions, Liley in 1965^^
suggested that Rh isoimmunization could be readily managed via amniocentesis
and intrauterine fetal blood transfusions. His experience suggested "that
fetal transfusion could ensure survival of some 70 percent of otherwise fatally
affected erythroblastotic babies, but that survival falls to zero if treatment
is delayed until the development of gross hydrops and ascites." This became
a landmark development in the history of amniocentesis.
Genetic Defects. In 1949, Barr and Bertram® demonstrated that neurons
obtained from the brain, spinal cord or sympathetic ganglia of mature cats of
both sexes could be readily sorted into two groups even without prior knowledge
of the sex. This observation set the stage for human sex determination in fetal
cells .
In 1955, Marberger et al.,^^ and Moore and Barr^^ demonstrated that sex
chromatin could also be detected in desquamated cells from mucous membranes.
This discovery precipitated the idea that the cells of the amniotic fluid might
indicate the sex of the fetus. Toward the end of 1955, within a period of five
weeks, four groups of investigators independently developed the antenatal deter-
mination of fetal sex in amniotic fluid .^^^•^i°'^^'^'* This development was to be
very significant as regards the use of amniocentesis for the prenatal diagnosis
of sex-linked diseases. Finally, in 1950, Riis and Fuchs^ obtained amniotic
fluid for the antenatal sex determination from two mothers who were carriers of
an X-linked disease (hemophilia). Although, in both cases, the fetal sex deter-
mination on the amniotic fluid indicated a girl fetus, this was the prelude to
using amniocentesis to diagnose a prenatally heritable disease.
The first inborn error of metabolism was diagnosed via amniocentesis in
1955. Jeffcoate et al.,®^ showed that the adrenogenital syndrome could be ana-
lyzed in the amniotic fluid via the concentration of pregnanetriol at term from
affected pregnancies. However, a more recent study ^2 has shown that the disease
cannot be predicted during early or midpregnancy . Then, in 1955, another major
landmark occurred in the history of amniocentesis. This was the successful cul-
turing of fetal amniotic fluid cells by Steele and Breg^^^ and Thiede et al.,^-"^
in sufficient quantity to permit karotyping of the cells. In addition, this
would pave the way for studying other inborn errors of metabolism since many
of these diseases would be identified by measuring the absence of enzyme activ-
ity in cultured cells. In addition, during that same year Danes and Bearn^s
demonstrated that mucopolysaccharide storage disorders could be identified by
measuring the intracellular metachromasia in tissue cultures from patients suf-
fering from this disease. This would open the way for the intrauterine diagnosis
of these and related disorders.
In 1957, Jacobson and Barter ^2 published an article which postulated the
management of genetic defects via amniocentesis. They made the intrauterine
diagnosis of a D/D translocation carrier at 17 weeks gestation after they had
shown the mother to be a D/D translocation carrier. In their study, although
the D/D translocation had been identified and the fetal cells karotyped, the
mother elected to carry the pregnancy to term. Postnatal studies confirmed the
correct diagnosis of the fetus, i.e., a D/D translocation carrier. Earlier,
two simultaneous abstracts by Jacobson ^i and Turner ^20 ^^(j shown that the pre-
natal diagnosis of chromosomal translocations could be of definite assistance
in the management of genetic defects.
These studies were followed by the first therapeutic abortion of a Down's
syndrome fetus by Valenti et al., in 1968.122 T^e fetal cells, obtained from a
balanced carrier of a D/G chromosome translocation during the eighteenth week of
pregnancy, were analyzed after 22 days of in vitro cultivation. The karotypes
indicated a D/G fusion chromosome characteristic of Down's syndrome. The preg-
nancy was interrupted on this basis and a male fetus was delivered which showed
the dermatoglyphic and anatomic changes compatible with the prenatal diagnosis.
15-37
That same year Nadler ^8 successfully diagnosed Down's syndrome at 10 weeks'
gestation by chromosome analysis of cultivated amniotic fluid cells obtained
just prior to the therapeutic abortion.
As can be seen from the foregoing paragraphs, the use of amniocentesis
in the prenatal diagnosis of genetic defects was expanding rapidly. Additional
significant events in 1968 and 1969 included the following: (1) the in utero
identification by Fujimoto et al.,*^ of a fetus heterozygous for the Lesch-
Nyhan syndrome, an X-linked metabolic disease. This was identified via cultured
amniotic fluid cells; (2) the first diagnosis of an inborn error of metabolism
(galactosemia) in cultured amniotic fluid cells by Nadler.^^ The significance
of this development was that the inborn error was identified by showing the
absence of normal enzyme activity in the cultured cells,-'*-' (3) the first intra-
uterine diagnosis of Hurler's and Hunter's syndrome in cultured amniotic fluid
cells by Fratantoni et al."" Both of these syndromes involve genetic disorders
of mucopolysaccharide metabolism with Hurler's syndrome being an autosomal reces-
sive disease and Hunter's syndrome, an X-linked recessive disease; and (4) the
in utero detection of Type II glycogenosis (Pompe's disease) by Nadler and
Messina^^ on uncultured amniotic fluid cells. They point out that the ability
to use uncultured cells for the detection of enzyme activity (i.e., the absence
of a-1 ,4-glucosidase activity in fetal cells) permits rapid identification of
the affected fetus, drastically reduces the time interval between amniocentesis
and diagnosis, and obviates the need for specialized tissue culture technique.
The use of amniocentesis in prenatal genetic diagnosis expanded rapidly
during the sixties. The significant events since 1969 include the following:
(1) The prenatal diagnosis of Tay-Sachs disease (a Gmj ganglio-
sidosis disease) by Schneck et al., in 1970.1°*
(2) The demonstration by Holenberg et al.,58 in 1971 that human
fetuses could synthesize hemoglobin A suggested that genetic
counseling for disorders of hemoglobin (i.e., sickle cell
anemia and homozygous beta thalassemia) might be possible.
Kan et al.,^* in 1972 extended this observation by detecting
the sickle cell trait in a 15-week-old fetus of a mother who
also had the sickle cell trait. In their studies, blood
was either obtained from the umbilical cord of the fetus
at the time of therapeutic abortion or from the placenta,
obtained accidentally during amniocentesis for Rh incompat-
ibility at the end of the eighth month of pregnancy.
(3) The discovery by Brock and Sutcliffei^ in 1972, that a cor-
relation exists between a raised a-f etoprotein level in the
amniotic fluid and severe neurological defects in the fetus.
Fetal Maturity. Amniocentesis has been used for determining fetal matur-
ity and the significant chronological events include the following:
(1) The method of Brosens and Gordon in 1966^^ for estimating
fetal maturity via the cytologic examination of the amniotic
15-38
fluid. They were able to determine the percentage of
amniotic fluid cells, i.e., cells containing lipid sub-
stances stained orange when exposed to Nile blue sulfate.
An increase in the percentage of cells taking this stain
was observed after 38 weeks' gestation.
(2) The association of fetal maturity and the disappearance of
bilirxibin in unsensitized pregnancies by Mandelbaum et al.,
in 1967.^^ They observed a precipitous decline and disap-
pearance of the absorbance bulge at 450 my at 35 to 38
weeks' gestation.
(3) Another development in 1957 was the relationship demon-
strated by Pitkin and Zwrick*® between the amniotic fluid
creatinine concentration and gestational age. With
increasing fetal age there was also an increase in the
amniotic fluid creatinine.
C4) An association between gestational age and osmolality
was made by Miles and Pearson in 1959.^3 They reported
a downward trend in osmolality with gestational age and
stated that an osmolality less than 250 milliosmoles/L
was suggestive of fetal maturity.
(5) The discovery by Gluck et al.,5i in 1971 that the respira- ..
tory distress syndrome could be detected via amniocentesis.
Their studies showed that changes in phospholipids in amni-
otic fluid reflect those changes occurring in the developing
fetal lung. A sudden increase in the lecithin concentration
after 35 weeks indicates maturity of the pulmonary alveolar
lining, and the respiratory distress syndrome should not
occur if the fetus is born at this time.
Contribution of Human Fetal Research
to Amniocentesis
Technique
In the early usage of amniocentesis on humans, it soon became apparent
that the transcervical and transvaginal (both fornix anterior and fornix pos-
terior) approaches to the amniotic sac were unduly traumatic, unless performed
at term. 29 The most significant complications were induced premature labor
and/or hemorrhage. More recent investigation has confirmed these observa-
tions. ^'^■''^•sO'Ss.ios Consequently, transabdominal invasion of the amniotic sac
became the method of choice to withdraw amniotic fluid. As a direct result of
human investigations, this method has been refined in several areas as described
below. These refinements have resulted in what is now an accepted medical pro-
cedure when indicated, with minimal risk to both the mother and the fetus .^^
15-39
Before the introduction of ultrasound, palpation^ was the generally
accepted method of determining fetal and placental position, although amniog-
raphy was and still is used in some cases, usually during the third trimester.
It soon became evident that a fairly high degree of technical competence was
required to avoid complications such as placental or fetal puncture. The oper-
ation should be performed by an experienced obstetrician. The need for strict
aseptic procedures to avoid various types of sepsis became apparent. Some
advocate virtual surgical type conditions even though the operation is routinely
performed as an outpatient or office procedure. The optimum site for puncture
is still not agreed upon but as pointed out before, the prime criterion is
avoidance of the placenta and fetus.
The type and degree of sharpness of the needle has resulted from human
evaluation. It is generally agreed that a needle with a relatively obtuse
angled tip and low degree of hone is useful in ascertaining the layers of tis-
sue being traversed and determining when the amniotic cavity is entered. Many
recommend the use of a 22-gauge or smaller needle to minimize abdominal trauma
while others advocate an 18-gauge needle to traverse the maternal skin and sub-
cutaneous tissue. A 20-gauge needle is then inserted through the larger needle
into the amniotic cavity. The latter procedure supposedly further reduces the
possibility of sepsis.
The introduction of ultrasonography in obstetrics ,^° almost simultaneously
with midtrimester amniocentesis, inevitably resulted in the use of this method
to localize the placenta and fetus. Palpation for this purpose is often dif-
ficult at 14 to 18 weeks when amniotic taps are made for diagnosing congenital
disorders. Many now use ultrasound routinely prior to amniocentesis in order
to minimize procedural risks.
Airaiioscopy and fetoscopy, although not directly related to amniocentesis,
have been developed as a result of a desire to increase the knowledge of the
intrauterine environment, heretofore only available by amniocentesis. These
potentially useful diagnostic tools would, therefore, not have been developed
without the interest in amniotic fluid generated by utilizing amniocentesis.
Diagnostic and Therapeutic Procedures
Amniocentesis as a procedure was developed through research involving
living human fetuses over a period extending back to at least 1882. As pre-
viously noted, the major impact of the procedure has been to provide a means
of obtaining amniotic fluid so that diagnostic tests and therapeutic methods
could be performed during either the second or third trimester of pregnancy.
A total of thirty congenital anomalies can presently be detected in utero
during the second trimester of pregnancy, i.e., three X-linked disorders (see
Table 1), eight chromosomal aberrations (see Table 2), and sixteen inborn errors
of metabolism (see Table 3) . The detection of anomalies is dependent upon
determining the sex chromatin of the fetal cells, being able to karotype the
cells, or being able to culture the cells obtained in amniotic fluid. In the
case of the inborn errors of metabolism, many different enzyme assays are crit-
ical for determining the metabolic defect in the cultured cells.
15-40
The estimation of fetal maturity is made by the quantification of certain
compounds in the fluid such as bilirubin, creatinine, lecithin, and sphingomye-
lin and by staining exfoliated fetal cells with Nile blue sulfate. These sub-
stances are a direct result of the fetus' metabolism. The hemolytic problems
are associated with the degree of anemia in the fetus resulting from transfer
of Rh antibodies from the mother to the fetal circulation. In this situation,
the contribution of living human fetuses has been in the area of intrauterine
transfusions which serve the purpose of correcting the anemia present in the
fetus . . .; •: I ^ ;-.'-, . • \.
Additional contributions of human fetal research in the development of
amniocentesis for therapeutic purposes occurred in the correction of polyhydram-
nios and the induction of abortion.
Effect of Retrospective Ban on Human
Fetal Research on Amniocentesis
Technique ' -■..:'
The only animal models which might be suitable for developing the tech-
nique of transabdominal amniocentesis would have to be monovular and possess a
unicornuate uterus. ^^ This statement is based upon the fact that the technique
could not be satisfactorily evaluated either in uteri containing multiple
fetuses or in a bicornuate uterus because of the obvious structural differences
relative to humans. These restrictions reduce the potential animal models to
higher primates, e.g., monkeys, chimpanzees or baboons.
However, some suggest that even these higher primates do not serve as
satisfactory models for the following reasons :
(1) Significant difference in the amniotic fluid: fetal size
ratio relative to humans leading to invalid extrapolation
of a technique developed in these animals to humans ■
(2) Difference in skin and subcutaneous tissue composition
such that development of skill by the operator would
not be applicable to humans
(3) Difference in boney pelvis structure to the extent that
this hard tissue, in many cases, would not allow invasion
of the uterus at the desired human site-^^
(4) Placental position in some of these species is character-
istically anterior so that transabdominal entry into the
uterus would always be through the placenta ^^
(5) Size of the uterus is always smaller at equivalent stages
of pregnancy
15'-41
(6) Size differences also introduce the problem of needle
diameter and length. Properly sized needles for humans
could not be determined without direct evaluation on
humans .
As a result of human amniocentesis, many investigators are now routinely
performing amniocentesis in monkeys and other subhuman primates (e.g., Ref. 97).
This would lead one to believe that indeed the higher primates could have been
used as models to perfect the technique. However, the reasons cited above are
considered valid by some investigators and the technique for later second and
third trimester amniocenteses could never be perfected in these primates because
their offsprings never obtain an equivalent size.
It is true that the technique of withdrawing amniotic fluid insofar as
identification of the tissue layers and avoidance of the placenta and fetus
could have been developed using gravid human cadavers. The obvious problems
of the supply of fresh cadavers whose death did not involve or disturb the
fetal surroundings makes this an impractical solution. Even if a reasonable
supply were available, situations of bleeding and fetal motion could not be
analyzed in a cadaver. In any event, nothing would be learned as to possible
effects on the outcome of the fetus.
In conclusion, a ban on human fetal research with regard to developing
improved techniques of amniocentesis would have resulted in its nonutilization
due to inadequate or inappropriate alternate models with which to develop and
perfect the method. The ramifications of the unavailability of this technique
are overwhelming considering the multitude of highly useful and desirable diag-
nostic and therapeutic procedures which rely on amniocentesis. These procedures
are discussed below.
Diagnostic and Therapeutic Procedures
If it is accepted, as in the preceeding section, that the development of
amniocentesis was dependent upon research involving living human fetuses, the
effects of a ban on human fetal research in the antenatal diagnosis and therapy
via amniocentesis would have been far reaching indeed.
The contributions of human fetal research to the development of amniocen-
tesis as an accepted clinical procedure have included the following:
(1) Detection of genetic defects
(2) Detection of Rh isoimmunization
(3) Detection of fetal maturity
(4) Relief of polyhydramnios
(5) Induction of a therapeutic or elective abortion.
15-42
The effect of a ban on human fetal research involving the respiratory
distress syndrome and Bh isoimmunization will be covered in other sections of
this report. The development of these antenatal diagnostic tests and therapeu-
tic procedures would have been affected to the extent of the contribution of
amniocentesis in humans to each.
An important question in determining the effect a ban on human fetal
research would have on the prenatal diagnosis and therapeutic procedures devel-
oped as a result of amniocentesis, is whether or not an animal model could have
been substituted for the advances made to date. Each of the above indications
for performing amniocentesis will be considered.
Detection of Genetic Defects. There are no known animal models for iden-
tifying the X-linked diseases presently detectable by amniocentesis in the human.
The diseases detectable in utero include the Lesch-Nyhan and Hunter's syndromes,
and Fabry's disease. Other animal models may possess X-linked diseases but the
gene makeup is completely different from the human. Since X-linked diseases
are detected by biochemical means, if the gene makeup is different, there would
be no association between other species and their X-linked diseases and those
X-linked diseases detectable in humans. The same situation would prevail for
the cytogenetic studies used to detect chromosomal aberrations since the chro-
mosomal number and gene content is different. Thus, a suitable animal model
does not exist for detecting chromosomal aberrations. In addition, there is
no animal model for the various inborn errors of metabolism which have been
identified by antenatal diagnosis.
A recent study^^ has identified a model for the antenatal diagnosis of
spina bifida in the Lewis rat. This is of importance since a number of inves-
tigators ^"^-^^^-^^^-'^ have recently stressed the importance of the assay of alpha-
fetoprotein in the amniotic fluid in pregnancies in which the fetus had
anencephaly, myelomeningocele, or spina bifida. Thus, there may be an animal
model available for the detection and study of neural tube defects.
Fetal Maturity. The use of primates as a model for determining fetal
maturity has been attempted. ^^ Although amniotic fluid creatinine levels in
the last third of pregnancy in Macaca mulatta are comparable to values in
patients, no clear relationship exists between the creatinine concentration
and the duration of pregnancy. Similarly, the bilirubin concentration in the
amniotic fluid does not show a change with reference to gestational age.
The use of amniocentesis in diagnosing the respiratory distress syndrome
is discussed in another section.
Polyhydramnios . The polyhydramnios condition has been observed in
diabetic monkeys ,^6 and, as a result, amniocentesis could therefore be per-
formed on such a species to demonstrate the effect of fluid removal. However,
a primary disadvantage in using monkeys as a polyhydramnios model would be
the difficulty in breeding primates which are in captivity and developing a
colony of diabetic monkeys.
Induction of Abortion. Any of the higher primates presumably could be
used for developing the abortifacients to be used for inducing an abortion in
conjunction with amniocentesis. However, regarding the amniocentesis procedure
itself, the higher primates are considered an unsatisfactory model for reasons
cited earlier.
Outlook for Amniocentesis as a Clinical Procedure
Future of Technique
The technique of amniocentesis has reached a state of refinement such that
it is now an accepted medical procedure with several medical indications for its
use. The safety of the procedure will increase further with the widespread use
of ultrasonography to locate the placenta and position of the fetus. Amniocen-
tesis performed in conjunction with fetoscopy is also a real possible future
development. 86 This technique would reduce the incidence of injury to the fetus
and, in addition to obtaining amniotic fluid, would allow direct visual examina-
tion of the intrauterine cavity.
Some refinements in the technique as it now exists may be possible. For
example, the method of using an 18-gauge needle as a speculiom through the abdom-
inal tissue and the myometrium followed by insertion of a blunted plastic cath-
eter into the amniotic sac for obtaining the fluid might decrease the incidence
of fetal puncture. Indeed, Mann in 1965 and 1966 proposed the use of a plastic
catheter to reduce the risk of fetal injury (see Table 5) . Special needles
designed sepcifically for amniocentesis may also be developed since spinal needles
are the most commonly used now. The development of a small ultrasonic transducer
in direct conjunction with the puncture procedure is already under way^^^ and may
prove to be a useful adjunct to complete abdominal ultrasonic screening prior to
the operation.
Possible Effects of Amniocentesis on Future Medical Developments
As Milunsky et a.!.,^^ state, "the advent of prenatal diagnosis through
amniocentesis represents the most important advance so far attained in the
prevention of the births of infants with irreparable genetic mental defect and
fatal genetic disease." The antenatal diagnosis of specific X-linked diseases,
chromosomal aberrations, and metabolic disorders via amniocentesis has been
used effectively during the last ten years. The treatment of genetic disease
via amniocentesis in the future will depend upon many factors. Some of these
factors would include: (1) further improvements in the procedure itself;
(2) the development of special centers devoted solely to antenatal studies;-^^^
(3) the development of new diagnostic tests for the specific disease in ques-
tion ;'8 (4) further improvements in the culture medium and tissue culture
techniques; and (5) the development of other instrumentation or ancillary pro-
cedures which might be used in conjunction with amniocentesis.
At the present time, amniocentesis is concerned largely with detection,
but future developments may see more therapeutic uses of amniocentesis, i.e.,
the injection of materials or deficient substances directly into the fetal
circulation, peritoneal cavity, or amniotic fluid. In addition, just as amnio-
centesis has assisted in the development of other procedures, e.g., ultrasound
and amniography, the use of amniocentesis may assist in the development of
better procedures for detecting bone development and fetal head size.
In conclusion, genetic counseling is now possible for a number of diseases.
More importantly, this counseling can now be based upon actual in utero diag-
noses via amniocentesis rather than by previous calculated probability risks.
15-45
REFERENCES
1. Anon., "Amniocentesis," Brit. Med. J. 2:136, July 18, 1964.
2. Anon., "Amniocentesis: Indication, Technic, and Complications," ACOG Tec.
Bulletin 8, June 1968.
3. Anon., "Antenatal Diagnosis of Congenital Disorders," ACOG Tech. Bulletin
19, 1972.
4. Allen, H.H., et al., "Infants Undergoing Antenatal Diagnosis: A Prelimin-
ary Report," Am. J. Ob. Gyn . 118 (No. 3): 310, Feb. 1, 1974.
5. Alpern, W.M. , "Techniques of Amniocentesis," in Amniotic Fluid, S. Natelson
and A. Scommegna, editors, New York: Wiley and Sons, 1974, p. 201.
6. Asensio, S.H. and Pelegrina, I. A., "Transabdominal Amniocentesis: Evalua-
tion of a Procedure," Bol . Assoc. Med. P. Rico 60(No. 1):6, 1968.
7. Bang, J. and Northevel, A., "A New Ultrasonic Method for Transabdominal
Amniocentesis," Am. J. Ob. Gyn. 114(No. 5):599, Nov. 1, 1972.
8. Barr, M.L. and Bertram, E.G., "A Morphological Distinction Between Neurons
of the Male and Female and the Behavior of the Nucleolar Satellite During
Accelerated Nucleoprotein Synthesis," Nature (London) 163:676, 1949.
9. Berner, H.W. , "Amniography , An Accurate Way to Localize the Placenta," Ob.
Gyn. 29 (No. 2):200, Feb., 1967.
10. Berner, H.W., Seisler, E.P., and Barlow, J., "Fetal Cardia Tamponade: A
Complication of Amniocentesis," Ob. Gyn. 40(No. 4):599, Oct., 1972.
11. Bevis, D.C.A., "Blood Pigments in Haemolytic Disease of the Newborn," J. Ob.
Gyn. Brit. Comm. 63:68, 1956.
12. Bienerz, J., "Diagnostic Value of Ultrasonography in Obstetrics and Amniotic
Fluid Sampling," in Amniotic Fluid, S. Natelson and A. Scommegna, editors.
New York: John Wiley and Sons, 1974, p. 205.
13. Blajchman, M.A. , et al . , "Diagnostic Amniocentesis and Fetal-Maternal
Bleeding," Lancet 993, May 1974.
14. Bodensteiner , J.B. and Zellweger, H. , "Mongolism Preventable by Amniocente-
sis," Clin. Fed. 10(No. 10):554, 1971.
15. Brock, D.J.H. and Sutcliffe, R.G., "Alpha- fetoprotein in the Antenatal
Diagnosis of Anencephaly and Spina Bifida," Lancet 2:197, 1972.
15-46
REFERENCES (Continued)
15. Brosens, I. and Gordon, H. , "Estimation of Maturity by Cytological Examina-
tion of the Liquor Amnii," J. Ob. Gyn . Brit. Comm. 73:88, 1966.
17. Burnett, R.G. and Anderson, W.R., "The Hazards of Amniocentesis," J. Iowa
Med. Soc. 58 (No. 2):130, Feb., 1968.
18. Caldeyro-Barcia, R. , Pose, S.V., and Alvarez, H. , "Uterine Contractility
in Polyhydramnios and the Effects of Withdrawal of the Excess of Amniotic
Fluid," Am. J. Ob. Gyn. 73 (No. 6): 1238, J\ine 1957.
19. Cederbaum, S.D., et al., "Spontaneous Abortion and Hemorrhage Following
Attempted Amniocentesis in a Carrier of Hemophilia," Lancet 2:429,
Aug. 21, 1971.
20. Cook, L.N., et al., "Fetal Complications of Diagnostic Amniocentesis: A
Review and Report of a Case with Pneumothorax," Ped. 53(No. 3):421,
Mar., 1974. ■ ■ • •
21. Coombs, R.R.A., et al., "A and B Blood Group Antigens on Human Epidermal
Cells," Lancet 1:461, 1956.
22. Creasman, W.T., et al., "Fetal Complications of Amniocentesis," JAMA
204(No. 11):91, June 10, 1968.
23. Cross, H.E. and Maumenee , A.E., "Ocular Trauma During Amniocentesis," Arch.
Ophthal. 90:303, Oct., 1973.
24. Crystle, CD. and Rigsby, W.C. , "Amniocentesis: Experience and Complica-
tions," Am. J. Ob. Gyn. 106{No. 2):310, June 15, 1970.
25. Danes, B.S. and Beam, A.G., "Hurler's Syndrome. A Genetic Study in Cell
Culture," J. Exp. Med. 1:123, 1966.
25. Davidson, R.G. and Rattuzzi , M.C., "Prenatal Diagnosis of Genetic Disorders:
Trials and Tribulations," Clin. Chem. 18(No. 3):179, Mar., 1972. '■
27. DeMars, R. , et al., "Lesch-Nyhan Mutation: Prenatal Detection with Amniotic
Fluid Cells," Science 154:1303, June 13, 1969.
28. DeMeyer, W. and Baird, I., "Mortality and Skeletal Malformations from Amnio-
centesis and Oligohydramios in Rats: Cleft Palate, Club Foot, Microstomia,
and Adactyly," Teratology 2(No. 1):33, Feb., 1959.
29. Dieckmann, W.J. and Davis, M.E., "The Volumetric Determination of Amniotic
Fluid with Congo Reed," Am. J. Ob. Gyn. 25(No. 5):623, May 1933.
30. Donald, I., "Ultrasonic Echo Sounding in Obstetrical and Gynecological
Diagnosis," Am. J. Ob. Gyn. 93(No. 7):935, Dec. 1, 1965.
15-47
REFERENCES (Continued)
31. Doran, T.A. , et al., "The Antenatal Diagnosis of Genetic Disorders," Am. J.
Ob. Gyn. 118(No. 3):314, Feb. 1, 1974.
32. Dorfman, A., "Antenatal Diagnosis," The University of Chicago Press, Chicago,
286, 1972.
33. Edwards, J.H., "Uses of Amniocentesis," Lancet 1:608, Mar. 21, 1970.
34. Ekgren, J. and Moe , N. , "Transabdominal Isthmic Amniocentesis in Rh-
Immunization with Particular Reference to Complications," Acta Ob. Gyn.
Scand. 53 (No. 3):263, 1974.
35. Fairweather, D.V.I. , "Techniques and Safety of Amniocentesis," in Amniotic
Fluid: Research and Clinical Application, D.V.I. Fairweather and
T.K.A.B. Eskes, editors, Amsterdam: Excerpta Medica, 1973, p. 21.
36. Fairweather, D.V.I. , et al . , "Possible Immunological Implications of Amnio-
centesis," Lancet 2:1190, Dec. 7, 1963.
37. Fairweather, D.V.I, and Walker, W. , "Obstetrical Complications in the Routine
Use of Amniocentesis in Immunized Rh Women," J. Ob. Gynaec. Brit. Comm.
71:48, 1964.
38. Fort, A.T., "Prenatal Intrusion into the Amnion," Am. J. Ob. Gyn. 110(No. 3):
423, 1971.
39. Foulds, J.W. and Pennock, C.A. , "Amniotic Fluid Creatinine: An Unreliable
Index of Fetal Maturity," J. Ob. Gynaec. Brit. Comm. 79(No. 10):911, 1972.
40. Fratantoni, J.C., et al., "Intrauterine Diagnosis of the Hurler and Hunter
Syndromes," New Eng . J. Med. 280(No. 13):686, 1969.
41. Free, K. and McDonnell, B., "Rhesus Incompatibility - An Assessment of the
Hazards of Amniocentesis and the Effect of Liquor Volumes on Amniocentesis
Prediction," ;iust. W.Z. J. Ob. Gynaec. 10 (No. 3): 139, Aug., 1970.
42. Freeman, R.K. and Kreitzer, M.S., "Current Concepts in Antepartum and Intra-
partum Fetal Evaluation," in Current Problems in Pediatrics , Chicago:
Year Book Medical Publishers, Inc., 2 (No. 9):8, 1972.
43. Friedman, T.B., et al., "Galactosemia and Galactonolactone : Further
Biochemical Observations," Science 764, Feb., 1974.
44. Fuchs , F. , "Genetic Information from Amniotic Fluid Constituents," Clin.
Ob. Gyn. 9:565, 1966.
45. Fuchs, F., "Amniocentesis and Abortion: Methods and Risks," Birth Defects:
Original Series VII (No. 5):18, Apr., 1971.
15-48
REFERENCES (Continued)
46. Fuchs, F. and Cederqvist, L.L., "Recent Advances in Antenatal Diagnosis by
Amniotic Fluid Analysis," Clin. Ob. Gyn. 13(No. 1):178, 1970.
47. Fuchs, F. and Riis, P., "Antenatal Sex Determination," Nature (London)
177:330, 1956.
48. Fuchs, F., et al., "Determination of Foetal Blood Group," Lancet 1:996, 1956.
49. Fujimoto, W.Y., et al., "Biochemical Diagnosis of an X-linJced Disease In
Utero," Lancet 2:511, 1968.
50. Gerbie , A.B., et al., "Amniocentesis in Genetic Counseling," Am. J. Ob.
Gyn. 109(No. 5):765, Mar. 1, 1971.
51. Gluck, L. , et al., "Diagnosis of the Respiratory Distress Syndrome by
Amniocentesis," Am. J. Ob. Gyn. 109 (No. 3):440, 1971.
52. Goodlin, R.C., "Diagnostic Abdominal Amniocentesis," Am. J. Ob. Gyn. 88 (No. 8)
1090, Apr. 15, 1964.
53. Goodlin, R.C. and Clewell, W.H., "Sudden Fetal Death Following Diagnostic
Amniocentesis," Am. J. Ob. Gyn. 118(No. 2):285, Jan. 15, 1974.
54. Goodner, D.M. , "Antenatal Diagnosis of Genetic Defects," J. Repro . Med.
10(No. 6) :261, 1973.
55. Gottesfeld, K.R., et al., "Ultrasonic Placentography - A New Method for
Placental Localization," Am. J. Ob. Gyn. 95(No. 4):538, 1966.
56. Hellman, L.M. and Pritchard, J. A., Williams Obstetrics, New York: Appleton-
Century-Crofts (Meridith Corporation) , 14th edition. Chapter 38, 1971.
57. Hellman, L.M. , et al., "Safety of Diagnostic Ultrasound in Obstetrics,"
Lancet 1:1133, 1970.
58. Hollenberg, M.D., et al., "Adult Hemoglobin Synthesis by Reticulocytes from
the Human Fetus at Midtrimester , " Science 174:698, 1971.
59. Horger, F.O., III and Hutchinson, D.L., "Diagnostic Use of Amniotic Fluid,"
J. Pediat. 75:503, 1969.
60. Jacobson, C.B. , "Reports of Abdominal Amniocentesis Safe 16 to 18 Weeks for
Patients at Risk," Obstet. Gynec. News 10:47, 1975.
61. Jacobson, C.B., "Gestational Management in Balanced Translocation Hetero-
zygotes," Proc. Ill Int'n'l. Cong, of Human Genetics, Chicago, Abstract
No. 171, 1966.
62. Jacobson, C.B. and Barter, R.H., "Intrauterine Diagnosis and Management of
"--otic Defects," Am. J. Ob. Gyn. 99(No. 6):796, 1967.
15-49
REFERENCES (Continued)
63. Jeffcoate, T.N. A., et al., "Diagnosis of the Adrenogenital Syndrome," Lancet
2:553, 1965.
64. Kan, Y.W., et al., "Detection of the Sickle Gene in the Human Fetus," New
Eng. J. Med. 287 (No. 1):1, 1972.
65. Kaser, O. and Kubli, F. , "Amniotic Fluid Examination in Late Pregnancy,"
J. Lut. Fed. Gyn. and Ob. 4:35, 1966.
66. Kubli, F., "Indikation, Technik and Klinische Interpretation der Abdominalen
Amniopunktion, " Geburtsch. Frauenheilk 22:134, 1952.
67. Landsteiner, K. and Wiener, A.S., "An Agglutinable Factor in Human Blood
Recognized by Immune Sera for Rhesus Blood," Proc. Soc . Exp. Biol. Med.
43:223, 1940.
68. Lewis, B.V. and Chapman, P.A. , "A Comparison of Techniques for Determining
Prenatal Sex from Liquor Amnii," J. Clin. Pathol. 27 (No. 8):639, Aug., 1974.
69. Liley, A.W. , "Liquor Amnii Analysis in the Management of the Pregnancy Com-
plicated by Rhesus Sensitization," Am. J. Ob. Gyn. 82:1359, 1961.
70. Liley, A.W., "Intrauterine Transfusion of Fetus in Haemolytic Disease,"
Brit. Med. J. 2:1107, 1963.
71. Liley, A.W. , "Use of Amniocentesis and Fetal Transfusion in Erythroblastosis
Fetalis," Pediat . 35:836, 1965.
72. Mackenzie, J.M., et al., "Midtrimester Abortion: Clinical Experience with
Amniocentesis and Hypertonic Instillation in 400 Patients," Clin. Ob. Gyn.
14:107, Mar. , 1973.
73. Maori, J.N. , et al., "An Antenatal Diagnosis of Spina Bifida in the Lewis
Rat," Nature (New Biol.) 246:89, 1973.
74. Makowski, E.L., et al., "Detection of Sex of Fetus by the Incidence of Sex
Chromatin Body in Nuclei of Cells in Amniotic Fluid," Science 123:542, 1956.
75. Mandelbaum, B. , "Amniocentesis Technic, Aplications, and Complications,"
Michigan Medicine, 209, Mar., 1970.
76. Mandelbaum, B. , et al., "Determination of Fetal Maturity by Spectrophoto-
metric Analysis of Amniotic Fluid," Ob. and Gyn. 29:471, 1967.
77. Mandelbaum, B. , et al., "Determination by Spectrophotometric Analysis of
Amniotic Fluid," Ob. and Gyn. 30:653, 1967.
78. Marberger, E., et al., "Oral Smears as a Method of Chromosomal Sex Determin-
ation," Proc. Exp. Biol. New York, 89:488, 1955.
15-50
■ REFERENCES (Continued)
79. Mariona, E.G., "Electronic Monitoring of Twin Gestations," Am. J. Ob. Gyn,
117 (No. 8) :1149, Dec, 1973.
80. McLain, C.R., "Araniography , a Versatile Diagnostic Procedure in Obstetrics,"
Ob. Gyn. 23 (No. 1):45, Jan., 1964.
81. Menees, T.O., et al., "Amniography : Preliminary Report," Am. J. Roentgen
24(No. 4) :363, 1930.
82. Merkatz, J.R., et al., "Prenatal Diagnosis of Adrenogenital Syndrome by
Amniocentesis," J. Pediat . 75:977, 1969.
83. Miles, P. A. and Pearson, J.W., "Amniotic Fluid Osmolarity in Assessing
Fetal Maturity," Ob. and Gyn. 34:701, 1969.
84. Milunsky, A., The Prenatal Diagnosis of Hereditary Disorders, Springfield,
Illinois: C.C. Thomas, 1973.
85. Milunsky, A., et al., "Prenatal Genetic Diagnosis," iVeti' Eng. J. Med.
283(No. 25):1370, Dec. 17, 1970.
86. Mohr , J., "Foetal Genetic Diagnosis," Development of Techniques for Early
Sampling of Foetal Cells," Acta Path. Microbiol. Scand. 73:73, 1968.
87. Moore, K.L. and Barr, M.L., "Nuclear Morphology According to Sex in Human
Tissues," Acta Anat . 21(No. 3):197, 1954.
88. Nadler, H.L. , "Antenatal Detection of Hereditary Disorders," Pediat.
42 (No. 6) :912, 1968.
89. Nadler, H.L., "Indications for Amniocentesis in the Early Prenatal Detection
of Genetic Disorders," Birth Defects 7(No. 5):5, 1971. y ■,,■■...■
90. Nadler, H.L. and Gerbie, A.B., "Role of Amniocentesis in the Intrauterine
Detection of Genetic Disorders," New Eng. J. Med. 282(No. 11):596,
Mar. 12, 1970.
91. Nadler, H.L. and Messina, A.M., "In Utero Detection of Type II Glycogenosis
(Pompe's Disease)," Lancet 2:1277, 1969.
92. Nelson, M.M. , et al., "Predictive Values of Amniotic Fluid Macrophages in
Gross CNS Defects," Lancet, 504, Mar. 23, 1974.
93. O'Leary, T.A. and Feldman, M. , "Amniotic Fluid Osmolality in the Determina-
tion of Fetal Age and Welfare," Ob. and Gyn. 36:525, 1970.
94. Ostergard, D.L. , "The Physiology and Clinical Importance of Amniotic Fluid,
A Review," Ob. Gyn. Survey 25:297, 1970.
REFERENCES (Continued)
95. Peterson, E.N., et al., "Sonography and Amniocentesis as Predictors of
Gestational Age and Fetal Growth in the Rhesus Monkey," Am. J. Ob. Gyn.
114(No. 7) :883, 1972.
96. Pitkin, R. and Zwirek, S., "Amniotic Fluid Creatinine," Am. J. Ob. Gyn.
98:1135, 1967.
97. Poswillo, D. , "Experimental First Trimester Amniocentesis in Nonhuman
Primates," Teratology 6{No. 2):227, 1972.
98. Renwick, J.H., "Widening the Scope of Antenatal Diagnosis," Lancet 2:336,
Aug. 16, 1969.
99. Riis, P. and Fuchs , F. , "Antenatal Determination of Foetal Sex in Prevention
of Hereditary Diseases," Lancet 2:180, 1960.
100. Robinson, A., "Intrauterine Diagnosis and Ultrasound," Lancet, Dec. 29, 1973.
101. Ryan, G.T., "Fetal Bleeding as a Major Hazard of Amniocentesis," Ob. Gyn.
40(No. 5):702, Nov., 1972.
102. Saifer, A., et al . , "Caveats of Antenatal Diagnosis of Tay-Sachs Disease,"
Am. J. Ob. Gyn. 115(No. 4):553, Feb. 15, 1973.
103. Saling, E., "Die Amniosckpie ein neues Verfahren ziim Erkennen von Gefahren-
zustanden des Feten bei noch stehender Fruchtblase, " Geburtsch. Frauen-
heilk 22:830, 1962.
104. Schatz, F. , "Eine besondere Art von einseitiger Polyhydramnie mit anderseitiger
Oligohydramnie bei eineiigen Zwillingen," Arch. Gynak. 19:329, 1882.
105. Schneck, L. , et al., "Prenatal Diagnosis of Tay-Sachs Disease," Lancet 1:582,
1970.
106. Schneider, E.T., et al . , "Myocoplasma Contamination of Cultured Amniotic
Fluid Cells: Potential Hazard to Prenatal Chromosomal Diagnosis," Science
184:477, Apr. 26, 1974.
107. Scrimgeour, J.B., "Other Techniques for Antenatal Diagnosis," in Antenatal
Diagnosis of Genetic Disease, A.E.H. Emery, editor, Baltimore: Williams
& Wilkins Co. , 1973.
108. Scrimgeour, J.B., "Amniocentesis: Technique and Complications," in Antenatal
Diagnosis of Genetic Disease, A.E.H. Emery, editor, Baltimore: Williams
S Wilkins Co., 1973, p. 11.
109. Seller, M.J., et al . , "Maternal Serum-Alpha-Fetoprotein Levels and Prenatal
Diagnosis of Neural-Tube Defects," Lancet 1:428, 1974.
15-52
REFERENCES (Continued)
110. Serr, D.M., et al., "Diagnosis of Sex Before Birth Using Cells from the
Amniotic Fluid," Bull. Res. Coun. Israel 5B:137, 1955.
111. Shettles, L.B., "Nuclear Morphology of Cells in Human Amniotic Fluid in
Relation to Sex of Infant," Am. J. Ob. Gyn. 71:834, 1956.
112. Steele, M.W. and Breg, W.R. , Jr., "Chromosome Analysis of Human Amniotic
Fluid Cells," Lancet 1:383, 1966.
113. Stetten, D. , "Centers for Genetic Counseling and Amniocentesis," in
Amniotic Fluid, S. Natelson and A. Scommegna, editors. New York: John
Wiley and Sons, 1974, p. 275.
114. Singh, S. and Singh, G., "Hemorrhages in the Limbs of Fetal Rats After
Amniocentesis and Their Role in Limb Malformation," Teratology 8:11,
Aug. , 1973.
115. Sutherland, G.R., et al., "Amniotic Fluid Macrophages and Anencephaly , "
Lancet, 1098, Nov. 10, 1973.
116. Thiede, H.A. , "Amniocentesis: A New Approach to So.me Old Problems in
Obstetrics," Surg. 67 (No. 2): 383, 1970.
117. Thiede, H.A. , et al . , "Antenatal Analysis of Human Chromosomes," Am. J.
Ob. Gyn. 94:589, 1966.
118. Trasler, D.G., et al., "Congenital Malformations Produced by Amniotic Sac
Puncture," Science 124:439, Sept. 7, 1956.
119. Turnbull, A.C. , et al., "Antenatal Diagnosis of Fetal Abnormalities with
Special Reference to Amniocentesis," Proc. Roy. Sac. Med. 66:1115, Nov.,
1973. • .
120. Turner, J., et al., "Chromosomal Studies on the Intrauterine Human Fetus,"
Proc. Ilird Int'n'l Cong, of Human Genetics, Chicago, Abstract 331, 1966.
121. Valenti, C. , "Endoamnioscopy and Fetal Biopsy: A New Technique," Am. J.
Ob. Gyn. 114(No. 4):561, Oct. 15, 1972.
122. Valenti, C. , et al., "Prenatal Diagnosis of Down's Syndrome," Lancet 2:220,
1968.
123. Walker, A.H.C., "Liquor Amnii Studies in the Prediction of Haemolytic
Disease of the Newborn," Brit. Med. J. 2:376, 1957.
124. Welt, S.I., "Antenatal Diagnosis via Amniocentesis," Am. J. Ob. Gyn.
117(No. 8):1149, Dec. 15, 1973.
15-53
REFERENCES (Continued)
125. Westin, B. , "Hysteroscopy in Early Pregnancy," Lancet ii:872, 1954.
126. Winiewski, L. , "Alpha-Fetoprotein in Amniotic Fluid in Early Normal
Pregnancy and Intrauterine Fetal Death," Brit. Med. J., 742,
Sept. 21, 1974.
Principals Interviewed
Dr. Henry Nadler
Chief of Staff
Children's Memorial Hospital
Chicago, Illinois
Dr. Cecil Jacobson
Department of Obstetrics
George Washington University
School of Medicine
Washington, D.C.
Dr. Leandro Cordero
Department of Pediatrics
The Ohio State University
College of Medicine
Columbus, Ohio
Dr. Frederick Zuspan
Department of Obstetrics and Gynecology
The Ohio State University
College of Medicine
Columbus, Ohio
i-S<
< oc ir
^
Q
>
o
s
111
X
So
35
S 9
S 2
2 O
OS
«5z
J I LJ_
5>2
L
SCHATZ, 1882
INTRODUCED AMNIOCENTESIS F
THERAPY OF P
LHF
ANCILLARY PROCEDURES
HEMOLYTIC DISEASE
GENETIC DEFECTS
FETAL MATURITY
MENEES. 1930
INITIAL USE OF
DIAGNOSTIC AlC
AMNIOCnAPHV
LHF
WEST! N, 1954
tNTRODl
LHF
LHF
GOTTESFELD. 1966
USE OF ULTRASOUND F
LOCALIZATION
LHF
COOMBS. 1956
A&B ANTIGENS DEMONSTRATED l^
EPIDERMAL CELLS BY MIXED AGGI
FUCHS, 1966
DETERMINATION OF FETAL ABC B
GROUPS IN AMNIOTIC FLUID CELL!
DEMONSTRATING HEMOLYTIC DISEASE
FOR DETERMINING
blood lhf
miotic fluid
[""nations "
Looo LHF
LHF
isioN LHF
HN
H
LHF
N
CODES
HUMAN NEONATE
HUMAN
LIVING HUMAN FETUS
(INCLUDING MOTHER)
NONLIVING NEONATE OR
SPONTANEOUS ABORTION
(AUTOPSY)
ANIMAL
MORPHOLOGICAL SEX
lOOHt, ly^b MAHBtHUfcH. lass UW/U
ETECTION OF SEX CHROMATIN IN fllM/ri
ESQUAMATED MUCOUS MEM8RANE CELLS
1956: MAKOWSKI, 1956 |,HF
HRST TO USE ;
FCOATE 1965
LHF
MHST ANTENATAL IDENTIFICATION Of AN .NBORN I IJC
LHHOR OF METABOLISM DISEASE IN ^MNlOTlC l-"r
"LUIO,-e. THE ADRENC)GENITAL SYNDROME
■m"''.AHo%y7Nl''o/^ LHF
3ANES 1966
XHAfiltE LJ
;SUE CULTURES ■•
r~*^'"'.';' LHF
JIMOTO, 1968
tST DIAGNOSIS OF AN X-L
SCH NYHAN SYNDROMEI
NIOTIC FLUID CELLS
ED DISEASE ■ ijt
:uLTuRiNc i-nr
RED LHF
'/,;„"" LHF
I^t"""' LHF
ETUSES LHF
CORRELATION DEMONSTRATED BETWEEN A , , ,_
RAISED Q-FETOPROTEIN LEVEL IN AMNIOTIC LHF
FLUID AND SEVERE NEURAL TUBE DEFECTS
IN FETUS
LHF
LHF
: CONCENTRATION
LHF
LHF
SYNDROME BY MEA
IN AMNIOTIC FLUID
LHF
Figure 2. Historiograph - Amniocentesis
ISOIMMUNIZATION (Rh VACCINE)
Medical Significance
The discovery of the Rh factor and the simultaneous elucidation of erythro-
blastosis fetalis about 1940 is one of the great milestones of medical science.
Techniques have been developed within our lifetime which have effectively con-
trolled the threat of Rh isoimmune disease. These developments over the past
three decades have resulted not only in the savings of hundreds of thousands of
lives, but also in the successful circumvention of an appreciable number of brain-
damaged children.
It has been estimated that the total amount of money used to support Rh
disease research from 1930 through the successful development of the vaccine in
1965 is about what society pays today for lifetime care for a half-dozen children
irreparably brain-damaged by erythroblastosis.^^
Statistically, the problem of hemolytic disease of the newborn can be enu-
merated as follows: ..--■- .....
(1) Approximately 12 percent of all marriages in the United States
a.re between Rh- incompatible individuals.
(2) Of the 3.0 to 3.5 million births which occur yearly in the
United States, approximately 25,000 infants could be affected
by isoimmune hemolytic disease.
(3) The number of stillbirths occurring because of isoimmune hemo-
lytic disease prior to the 1940s was in excess of 10,000 per
year in the United States. The number decreased to less than
5,000 with the introduction of transfusion techniques. *° It has
been estimated that in the twenty-year period between 1940 and
1960, approximately 200,000 lives were saved by these techniques
alone. . ..• , , .
(4) World Health Organization statistics indicate that on a world-
wide basis even today 20-25 percent of Rh-positive infants of ■.-■,
already Rh-sensitized women are likely to be stillborn in the , . .^
last trimester. Worldwide statistics are however difficult to
determine because of the racial variation of the occurrence of
the Rh factor. ,. ,. .,
(5) As of 1973, approximately 88 percent of first-pregnancy, Rh-
negative women in the United States were receiving the Rh vac-
cine. Surveys showed 95-100 percent usage in urban areas and
as low as 65 percent in rural areas.
The technology developed in the search for an answer to the hemolytic
disease of the newborn provided a number of notable approaches and techniques
which have been and will continue to be extremely useful in the cure and detec-
tion of human diseases which may be unrelated to Rh disease. These include:
(1) The development of techniques to quantify bilirubin in the
serum of newborns so that brain damage due to excessive
release of blood pigments can be avoided.
(2) The initiation of amniocentesis for the detection of bili-
rubin in amniotic fluid. Amniocentesis is now useful for
detection and elucidation of a number of genetic disease of
man including a and 6 thalassemia and sickle cell disease ^°
and may have vast diagnostic potential.
(3) The initiation and perfection of the intrauterine transfusion
technique and the development of fetus visualization tech-
niques (fetology) now used for the detection of other malfor-
mations and/or diseases of the fetus, in utero.
One of the more important advancements to stem from the search for a cure
for Rh disease is the initiation of the cooperative participation of research
scientists and clinicians to obtain a common goal. This philosophical advance-
ment has resulted in the vastly increased efficiency of medical research teams
in their goal of the conquest of many of our most dread diseases.
Dr. Louis K. Diamond, one of the pioneering researchers in Rh disease,
summarized his feelings in these words at a recent interview: "At present what
is happening all over the country and all over the world for that matter, is a
close collaboration between the Ph.D. researcher and the clinician. This very
marked advance over my early days has proven the fact that many Ph.D. researchers
are not only happy to collaborate but are anxious to do so. They wish to prove
the usefulness of their bench work in terms of human therapy. This has uplifted
the laboratory researcher and made the physicians who limit themselves to clinical
work much more anxious to work at the bench to delineate the basic problems of
medical science. I believe that this type of cooperative research which combines
both clinical facilities and basic laboratory progress is the only rapid way of
advancing medical science. In my area it is necessary to combine the talents of
basic scientists who know enzymology, immunology, and cell structure with the
practical experience of the clinician. I believe that in my lifetime this result
has been the greatest advance in research."'"
This approach was used to its fullest extent in the conquest of Rh disease.
Due to this dedicated cooperation, researchers and clinicians not only elucidated
but also brought under control an extremely serious fetal disease in little more
than three decades.
Historical Account
Characterization of Erythroblastosis Fetalis
Although hemolytic disease of the newborn was described prior to the turn
of this century, the relationship between jaundice (icterus), hydrops, anemia
and eventually brain damage (kernicterus) in newborns was not established until
the early 1900s. ^*' ^^' ^''' ^^ The early reports were primarily disease descrip-
tions based on fetal autopsies. In 1932, Diamond et al., demonstrated that
erythroblastosis was the single disease underlying jaundice, hydrops, and
anemia.-''' Following this descriptive phase, a relationship between the level
of bilirubin in the infant's serum and kernicterus was established and methods
of bilirubin quantification were developed. ^' ^®> **■ ^® Siibsequent to these
developments, the presence of hyperbilirubinemia was shown to be directly
related to the delayed brain damage (kernicterus) noted in infants with erythro-
blastosis fetalis. 26
Etiology of Erythroblastosis Fetalis
Concurrent with disease interrelationships and their description, the major
blood groups (A, B, and 0) were recognized.'"^ Several additional blood group
isoantigens were identified prior to 1939,^'' ^^ when Levine and Stetson noted the \
presence of a non-ABO blood group antibody in the serum of a patient following
delivery of a stillborn infant.^^ iphg following year, it was observed that an
antiserum prepared in rabbits against an antigen on the erythrocytes of the rhesus
monkey reacted positively with 85 percent of human erythrocytes, which presiamably
contained the antigen, while 15 percent of those tested were negative. ^-^ This
non-ABO blood group antigen was termed the Rh antigen (subsequently shown to be
a system of antigens) .
In 1941, Levine et al., demonstrated that Rh sensitization in an Rh-negative
mother to an Rh-positive fetus was responsible for the disease pathologies asso- -
ciated with erythroblastosis fetalis. ^^ The protection against Rh sensitization
afforded by ABO incompatibility between the mother and fetus was postulated in
1943,^^ and subsequently substantiated by statistical analysis reported in 1958.^
Disease Detection
In the 1950s several procedures for detecting both fetal erythrocytes and/
or antibody to Rh-positive fetal erythrocytes in the maternal circulation proved
the relationship between Rh isoimmunization and erythroblastosis fetalis. Fetal
hemorrhage into the maternal circulation was documented in 1954 by demonstrating
the presence of agglutinins to an Rh-positive fetus in an Rh-negative mother. '
Placental transfer of fetal erythrocytes was shown the following year,"" and a
test developed to demonstrate the presence of fetal erythrocytes in the maternal
circulation. 2^
15-59
Several approaches to early disease detection were developed following
elucidation of the etiology of Rh hemolytic disease. The earliest of these
tests involved testing the mother's serum for the presence of incomplete Rh
antibodies.'' ^^ A second approach was based on the detection of bilirubin in
the serum of the neonate, ^^' ^^ and somewhat later in the amnionic fluid of the
mother.^ The feasibility of quantifying bilirubin in the newborn with jaundice
was demonstrated as early as 1916.*^ The establishment of the relationship
between bilirubin levels and brain damage in Rh hemolytic disease led to the
perfection of a micromethod for determination of bilirubin levels in the serum
of diseased infants. ^^ This assay provided a basis for the development of
exchange transfusion in the affected neonate.'^ The development by Bevis "* in
1956 of transabdominal aminocentesis for the purpose of determination of bili-
rubin levels in the amnionic fluid (spectrophotometric analysis) enabled Liley
to monitor more precisely the extent of hemolytic disease in the fetus, and led
eventually to Liley 's highly successful treatment of the diseased fetus in utero
by intrauterine transfusion.-'^
Another approach to detection of maternal Rh sensitization against incom-
patible fetal erythrocytes involved the demonstration of fetal cells in maternal
blood. ^^ This technique, introduced by Kleihauer in 1957, has been widely applied
to monitor the effectiveness of disease prophylaxis. It remains the major method
of demonstrating that a transplacental hemorrhage of fetal erythrocytes into the
maternal circulation has occurred.
Therapy of Erythroblastosis Fetalis
As noted in the previous section, the therapy of Rh hemolytic disease was
directly dependent on the perfection of accurate diagnostic procedures and eluci-
dation of the mechanism of the disease process and the resultant pathologic
manifestations .
The earliest surgical approach to disease treatment was exchange transfusion
of the affected neonate shortly after birth. The first successful exchange trans-
fusion was performed in 1925 for the disease then termed icterus gravis .^^ In the
1940s a great deal of experimentation was performed to perfect this procedure for
the early treatment of neonates with previously detected erythroblastosis fetalis.
Wiener'** reported on several successful exchange transfusions via the antecubital
vein in infants with erythroblastosis fetalis. Diamond et al., further refined
this procedure by using the more accessible umbilical vein and a clot-retarding
plastic catheter.^'' The extension of this method to multiple transfusions in the
diseased live newborn virtually eliminated the threat of brain damage, and the
mortality of neonates with erythroblastosis dropped to about 2.5 percent. ^°
However, the problem of the severely diseased fetus which usually died in
utero required a more sophisticated therapeutic approach. This advance became
possible following the perfection of amniocentesis to monitor accurately bilirubin
levels in the gravid sensitized female. Approximately 25 percent of Rh-positive
fetuses in Rh-sensitized females were destined to be stillborn. The intrauterine
transfusion introduced by Liley ^* in 1963 was directly responsible for eventually
15-60
preventing stillbirth in more than 60 percent of these cases. Adamsons et al.,
attempted without success to refine this procedure further via hysterotomy.^
The only additional therapeutic technique which has been applied to erythro-
blastosis fetalis is phototherapy.^® This type of therapy is used as an adjxmct
to exchange transfusion to control rising biliriibin levels in diseased neonates.
Prophylaxis of Erythroblastosis Fetalis
Rh sensitization generally occurs following the delivery of the first Rh-
positive infant to an Rh- incompatible, Rh-negative, female. Sensitization may
also occur due to a slow transfer of fetal erythrocytes across the placenta,
following an abortion, or may even be the result of a transfusion reaction.
Mechanistically, the sensitization process involves the formation of specific
Rh(D) antibody in the female to the Rh antigen on the fetal erythrocyte. In a
sensitized female , the 7S immunoglobulin can cross the placenta and lyse fetal
red cells. The formation of Rh antibody in the sensitized female is termed an
anamnestic response. The current protocol employed to prevent Rh sensitization
is based on an observation by Smith in 1909 ''■' that the presence of excess passive
antibody prevented active immunization to the corresponding specific antigen.
The natural protection afforded the fetus in the ABO-incompatible situa-
tion led several investigators to speculate on the possibility of simulating
this protection by administering serum containing Rh antibodies. Priority for
the original proposal that passively administered Rh-antibody at delivery might
prevent sensitization apparently belongs to Finn and his associates in Liverpool.
Two groups of investigators, Finn et al.,^^ and Freda et al.,^* administered Rh
antiserum to Rh-negative male volunteers, with the same conclusion, passively
administered Rh antibody could prevent sensitization.
The trials of the Rh vaccine in women at risk following delivery of a first
Rh-positive neonate began in New York and in Liverpool in 1954.^' ■'' Freda et al.,
demonstrated in a statistically significant study protection of Rh-negative women
following an Rh-positive birth by administration of Rh antibody prepared from
concentrated gamma globulin.^® The positive results of Clarke et al., (Liverpool
Group) are perhaps more dramatic due to the almost exclusive use of high-risk
individuals in their clinical trials.*
Dxiring this period the Rh vaccine (RhoGAM) , as it would eventually be
called, was being developed and was made commercially available in 1968. The
vaccine, 7S-anti-Rh antibody, was prepared from the plasma or serum of Rh sensi-
tized, Rh-negative individuals.
The concept of specific Rh antibody mediated suppression of immunization by
the Rh antigen was thus demonstrated aind the vaccine made available for general
use by 1968. This approach to prophylaxis has since been shown to be 100 percent
effective by following high-risk Rh-negative women through successful second
pregnancies, and minimal prophylactic doses have been established through exten-
sive clinical trials. ^°
15-61
Contribution of Human Fetal Research to the
Control of Rh Hemolytic Isoimmune Disease
This section specifically delineates historically the research in which
it was necessary to employ either the gravid female or the live fetus as a
research subject in order to obtain an understanding of the mechanism of Rh
isoimmimization, to diagnose erythroblastosis in utero, or to develop therapeutic
procedures. There was very little purposeful research performed upon the gravid
woman and/or her fetus \intil after the underlying hemolytic phenomenon of the
disease was correctly described through the use of autopsy of postmortem human
fetuses and/or newborns (a period extending from 1913 to 1929) . During this
time, approximately 20,000 to 25,000 newborns yearly were being affected by the
disease. Following this period, there are three major phases of the attack on
erythroblastosis which required human fetal research.
Etiology and Mechanism of Fetal or Neonatal Hemolytic Disease
Due to the unsuitability of available animal models (outlined specifically
in the section concerned with the effects of a ban on fetal research) it was
necessary to define the mechanism of erythroblastosis in the human situation.
This required that:
(1) It could be demonstrated that immature fetal red blood cells
(erythroblasts) could enter the maternal circulation and
induce antibody production. Chown characterized erythroblasts
in fetal fluids and in maternal blood using gravid females in
1954.^
(2) The theoretical nature of the immunological etiology of the
disease be proven by demonstrating that maternal anti-Rh
antibodies did cross the placental barrier to affect the
fetus. This was demonstrated by Mengert in 1955*° using
amniotic fluid drawn from the amnionic sac of a viable fetus
in utero.
(3) The role of bilirubin (the blood pigment, released during
hemolysis, which causes brain damage) in the fetus be defined
because it was known to cause neurological damage in the new-
born. Bevis in 1956 through use of the aminocentesis proce-
dure demonstrated that bilirubin levels were not destructive
to the fetus in utero but that upon birth the neonate could
not control pigment release by its own metabolism."
Detection of Fetal or Neonatal Hemolytic Disease
Once the disease mechanism had been extensively described it became neces-
sary to detect the extent of disease in susceptible gravid females. This required
a definitive series of events.
15-62
(1) Bevis's demonstration in 1956 that bilirubin levels could
be detected in fetal fluids drawn from the amnionic sac
of a viable fetus in utero provided a reliable technique.
(2) Billing and Lathe's (1958) full elaboration of bilirubin
biochemistry . ^
(3) The use of bilirubin levels in amniotic fluid drawn from
the fetal amnionic sac in utero by Liley to determine the
proper timing and type of therapy. -^^
Therapy of Fetal Hemolytic Disease _. . , .: ' -
Prior to the development of the above specific diagnostic techniques, it
was found that the technique of multiple exchange transfusions of the newborn
was effective in treating hemolytic disease and hyperbilirubinemia after a
successful delivery. This technique, however, was useless for the large number
of stillborns. Following animal studies and the demonstration that the bilirubin
detection technique was of diagnostic value, it was considered feasible to per-
form an exchange transfusion with the fetus while it still resided in utero.
This decision was followed by a number of attempted techniques:
(1) Transcutaneous approach into the fetal peritoneal cavity
(with the fetus lying in utero) to infuse red blood cells
was proven successful by Liley in 1964.
(2) Implantation of catheters under direct vision after partial
delivery of the fetus by hysterotomy was proven unsuccessful
by Adarasons et al . '
(3) The most successful technique which is now accepted as stan-
dard procedure is the intrauterine exchange transfusion.^^
These developments represent only preliminary milestones, most of which
were followed by extensive trials and modifications of techniques. In the con-
tinuum of research they represent turning points that could not have been opti-
mally achieved in any other fashion. The benefits of these research findings
are immeasurable. The perfection of the intrauterine transfusion technique
alone resulted in the successful rescue of 50 percent of the fetuses which were
previously destined for stillbirth due to hemolytic disease. The development of
aminocentesis as a reliable diagnostic tool has resulted in a tremendous broad-
ening of our knowledge of the fetal environment and of fetal maturation. It was
through this sequence of critical events in human fetal research that the Rh vac-
cine was conceived and the threat of Rh disease brought under control.
15-63
Effect of a Retrospective Ban on Human Fetal Research
on the Control of Ph Isoimmune Hemolytic Disease
The conquest of Rh disease through the elucidation of the disease, develop-
ment of effective diagnostic and therapeutic procedures, and eventual prophylaxis
of the disease represents one of the major medical achievements of this century.
The major portion of this progress occurred over a 30-year period. This is a
remarkably short period of time to perform the quantity and quality of research
generally required to gain an understanding of any complex disease process and
proceed to treat and/or prevent the disease.
The Rh vaccine (RhoGAM) has been clinically so effective in preventing Rh
sensitization that Dr. Louis K. Diamond believes that Rh disease will cease to
be a problem in this generation.^" There are of course small niimbers of presen-
sitized females, and transfusion accidents due to human error will occur, but
generally speaking Rh disease has been effectively controlled.
To assess the effects of a ban on fetal research on the ultimate conquest
of Rh hemolytic disease, predating the discovery of the Rh factor, the following
questions must be considered:
(1) Could the mechanism of the disease process have been determined?
(2) Would effective methods of disease detection have been developed?
(3) How would affected neonates have been treated?
(4) Could procedures have been developed to treat the fetus destined
to be stillborn, while still in utero?
(5) Would the Rh vaccine, now known to prevent sensitization in
cases of Rh incompatibility, have been developed and shown to
be effective?
The discovery of the Rh factor, and the ultimate elucidation of the mecha-
nism of isoimmune disease, did not involve hiaman fetal research during the period
of disease characterization or the early research which specifically linked Rh(D)
incompatibility to erythroblastosis fetalis. This research was performed pri-
marily on affected stillborn infants or neonates. However, to link unequivically
Rh incompatibility to erythroblastosis required the demonstration of fetal cells
in the maternal circulation and evidence of specific active immunologic reactiv-
ity against those cells. This ultimately required that gravid females be tested
for the presence of fetal cells prior to the onset of labor and sequentially
monitored for antibody levels throughout the gestation period. A ban on fetal
research would not have allowed this understanding of the mechanism of isoimmune
disease in humans to evolve over the short span of 15 years. Selected animal
models could have been used for study, but none closely mimicked human isoimmune
disease.
15-64
The animal models available for research during the period in which Rh
hemolytic disease was conquered will be considered in a later portion of this
section.
Soon after Rh incompatibility was postulated to be responsible for the
hydrops, anemia, jaundice, and brain damage associated with the disease process
designated erythroblastosis, it became apparent that methods of early detection
were the only possible means to predict the probability of disease in these
fetuses. Tests to assess the presence of Rh antibodies in the circulation of
the sensitized gravid female, and the presence and quantity of fetal erythrocytes
in the maternal circulation led to the development of prompt exchange transfu-
sions for neonates with erythroblastosis fetalis.
The principal method of early detection of Rh hemolytic disease of the
fetus in utero is based on the detection of bilirubin in amniotic fluid. The
development of amniocentesis enabled clinical investigators to detect erythro-
blastosis fetalis much earlier and led to the development of the intrauterine
transfusion for the high-risk fetus destined to be stillborn. These procedures
required that experimental procedures be performed on both the gravid female and
ultimately on the fetus in utero. •■ . ■
Thus, effective procedures for saving these infants both after birth and
in utero became available. A ban on fetal research might not have precluded the
development of the exchange transfusion or the intrauterine transfusion in
animals, and in fact animal models were employed to study these procedures prior
to human experimentation. However, in an absence of knowledge of the underlying
cause of the disease process, the application of these procedures in the treat-
ment of neonates and fetuses with erythroblastosis fetalis would certainly have
been greatly delayed and many fetuses and neonates, especially high-risk fetuses,
would certainly have been lost.
Although Rh antibody (IgG) administered to prevent sensitization following
the delivery of a first Rh-incompatible infant does not involve the fetus
directly, the development of this vaccine is intimately tied to fetal research.
All of the research areas in the conquest of erythroblastosis fetalis are inter-
related, and the impetus for a prophylactic approach is directly related to an
understanding of the disease mechanism and, of course, a desire to eliminate
the problem of the high-risk fetus.
In attempting to ascertain the effects of a retroactive ban on fetal
research on the control of Rh hemolytic disease, the availability of animal
models and their applicability as models in the various phases of this research
should be considered. During the course of the research which led to the ulti-
mate prevention of erythroblastosis fetalis, a nximber of animal models were con-
sidered based on several criteria.*
(1) Dog — availability, breeding ease, gestational period and the
existence of canine erythroblastosis.
(2) Rodent species (rat, mouse, rabbit) — availability, breeding
ease, and inducibility of hemolytic disease.
15-65
(3) Donkey or mule — large size of fetus and presence of patho-
logic erythroblastosis manifestations,
(4) Primates (chimpanzee and baboon) — system of comparable blood
group isoantigens and isoimmune hemolytic disease.
These models were employed in selected phases of the research but ulti-
mately rejected as models for Rh isoimmune hemolytic disease in humans for the
following reasons : *• '°
(1) Dog — dissimilar placental construction compared with humans;
there is no placental transfer of antibodies.
(2) Rodent species — small fetal size was prohibitive for surgical
procedures comparable to human situation and disease manifes-
tations were highly variable even within the same litter.
(3) Donkey or mule — disease pathology is similar but there is no
placental transfer of antibodies; antibodies were passed via
colostrum (milk) .
(4) Primates — the advent of intense research on the isoantigens
of primates and the mechanism of isoimmune disease in these
animals is a recent event. Although these animals may ulti-
mately prove to be adequate models for the study of iso-
immune hemolytic diseases similar to erythroblastosis fetalis,
the relative unavailability of the primate species, the vari-
ability of disease pattern as compared to the human disease,
and a lack of knowledge of the blood group isoantigens in
these species did not make them ideal models for the type of
research required to solve the Rh problem rapidly.
Although there certainly were areas where animal models may have been more
extensively employed, if there had been a ban or even a severe curtailment on
research involving living human fetuses or pregnant women, the knowledge required
for the development of the medical techniques for detection and treatment of Rh
hemolytic disease of the newborn would have been immeasurably delayed, and the Rh
vaccine as it is used today most probably would not have been possible. This
would have resulted in the stillbirth of approximately 450,000 fetuses over the
period from 1930 to 1975. Even more devastating would be the medical, social,
and economic impact that would have resulted from the birth of tens of thousands
of brain-damaged individuals over this same period.
Future Outlook
Future of the Procedures
The outlook for the successful management of Rh hemolytic disease is very
bright. With the current use of amniocentesis as a detective and diagnostic
tool it is possible to pinpoint with almost total accuracy the endangered fetus.
The early diagnosis of erythroblastosis fetalis can now be followed by either
early delivery, intrauterine transfusion, or exchange transfusion of the newborn.
These techniques are necessary only in those women who have been presensitized or
who have not received the Rh vaccine after the first pregnancy. For those women
who do receive the Rh vaccine upon the completion of their first pregnancy, the
problem of isoimmunization to their fetus and to subsequent fetuses is almost
completely eliminated. ...
Effects of Future Development on Other Areas of Medical Science
The use of human fetal research in the development of techniques of diag-
nosis, therapy, and prophylaxis and the generation of theoretical problems in the
search for an answer to Rh disease have resulted in the initiation of lines of
research which apply to a myriad of scientific and medical disciplines.
The monitoring of antibody levels in the serum of gravid females as well
as enzyme, pigment, and antibody levels in amniotic fluid has given researchers
powerful tools to describe genetic, maturational , and functional defects of the
fetus. The ability to apply Mendelian genetics to parental pairs has further
broadened our concept of inborn genetic disorders. With the perfection of fetal
and neonatal surgical procedures, it is now possible to attempt to correct cer-
tain of these disorders.
Future developments in the area of immunology requiring human fetal research
are based on many of the procedures developed during the course of solving the
problem of Rh hemolytic disease. Research has begun to attempt to understand and
control a variety of immune deficiency diseases. These diseases are generally
sex-linked disorders which cannot be reproduced in animal models. Current experi-
ments suggest that it may be feasible to monitor levels of T- and B-lymphocytes
and progenitor cells in the fetal circulation. It has been demonstrated that
transplantation of lymphoid tissues such as the thymus from aborted fetuses or
stillborn neonates may be an effective approach to treating these immunodeficiency
diseases.^' *^ In addition, fetal research is necessary to a better understanding
of the overall ontogeny of the immune response.
This type of research will facilitate the development of fetal surgery, in
which transplants may be carried out in utero. This could conceivably eliminate
the problem of organ transplants between HLA-incompatible individuals. This line
of research could of course eventually apply to a variety of congenital defects.
These future research developments will not be possible if there is a prospective
ban on fetal research.
15-67
REFERENCES
1. Adamsons, S.K., Freda, V.J., et al., "Prenatal Treatment of Erythroblastosis
Fetalis Following Hysterotomy," Pediatrics 35:848, 1965.
2. Allen, F. , Diamond, L. , et al. , "Erythroblastosis Fetalis. VI. Prevention
of Kernicterus," Amer. J. Dis . Child. 80:779, 1950.
3. Amman, A.J., Wara, D.W. , et al . , "Thymus Transplantation: Permanent
Reconstitution of Cellular Immunity in a Patient with Sex-Linked Combined
Immunodeficiency," New Eng. J. Med. 289:5, 1973.
4. Bevis, D.C.A., "Blood Pigments in Haemolytic Disease of the Newborn,"
J. Obstet. Gynaec. Brit. Comm. 63:68, 1956.
5. Billings, B.H. and Lathe, G.H., "Bilirubin Metabolism in Jaundice," Amer.
J. Med. 24:111, 1958.
6. Charles, A.G. (ed. ) , Rh Isoimmunization and Erythroblastosis Fetalis,
New York: Appleton-Century Crofts, 1969.
7. Chown, B. , "Anemia from Bleeding of the Fetus into Mother's Circulation,"
Lancet 1:1213, 1954.
8. Clarke, C.A., et al., "Prevention of Rh Haemolytic Disease," Brit. Med. J.
4:7, 1967.
9. Coombs, R.R.A., Mourant, A.E. , et al., "Rh Factor: Detection of Weak
'Incomplete' Rh Agglutinins: New Test," Lancet 2:15, 1945.
10. Diamond, L.K. , Interview.
11. Diamond, L.K. , "The Rh Problem Through a Retrospectroscope, " Amer. J. Clin.
Path. 62:311, 1974.
12. Diamond, L.K. and Abelson, N.M. , "The Demonstration of Anti-Rh Agglutinins,
an Accurate and Rapid Slide Test," J. Lab. Clin. Med. 30:204, 1945.
13. Diamond, L.K. , Allen, F.H., et al., "Erythroblastosis Foetalis: Treatment
with Exchange Transfusion," N. Eng. J. Med. 244:39, 1951.
14. Diamond, L. , Blackfan, R.O., et al . , "Erythroblastosis Foetalis: Its
Association with Universal Oedema of the Foetus, Leterus Gravis Neonatorum,
and Anaemia of the Newborn," J. Pediat . 1:269, 1932.
15. Ferguson, J.A. , "Erythroblastosis with Jaundice and Edema in the Newly Born,"
Amer. J. Path. 7:277, 1931.
REFERENCES (Continued)
16. Finn, R. , Clark, C.A. , et al., "Experimental Studies on the Prevention of
Rh Haemolytic Disease," Brit. Med. J. 1:1486, 1961.
17. Freda, V.J., "Prevention of Rh Disease," Haematologia 6:1, 1972.
18. Freda, V.J. and Gorman, J.G., "Antepartum Management of Rh Hemolytic Disease,"
Bull. Sloane Hosp. Women 8:147, 1962.
19. Freda, V.J. and Gorman J.G. , "Rh Factor: Prevention of Isoimmunization and
Clinical Trial on Mothers," Science 151:828, 1966.
20. Gold, E.R. and Butler, N.R. , ABO Haemolytic Disease of the Newborn, Baltimore:
The Williams and Wilkins Company, 1972.
21. Goldbloom, A. and Gottlieb, R. , "Icterus Neonatorum," Amer. J. Dis. Child.
38:57, 1929.
22. Hart, A. P., "Familial Icterus Gravis of the Newborn and Treatment," Can.
Med. Assoc. J. 15:1008, 1925.
23. Heyman, M. , Interview.
24. Hirsch, A., "Physiological 'Jaundice Preparedness' of the Newborn," .- t.
Z. Kinderheilk. 9:196, 1913.
25. Hsia, D.Y.Y., Hsia, H.H., et al . , "A Micromethod for Serum Bilirubin,"
J. Lab. Clin. Med. 40 (No. 4):610, 1952.
26. Hsia, D.Y., Allen, F.H., et al., "Erythroblastosis Fetalis: VII. Studies
of Serum Bilirubin in Relation to Kernicterus , " New Eng. J. Med. 247:668,
1952.
27. Kleihauer, E. , Braun, H. , and Betke, K. , "Demonstration von Fetalem Haemo-
globin in den Erythrocyten eines Blutansstrichs , " Klin. Wschr. 35:637,
1957.
28. Klieger, J.A. , "The Rh Factor: Past, Present, and Future," Med. Clin. North
Am. 53:1063, 1969.
29. Krevans , J.K. , Interview.
30. Landsteiner, K. , "Zur Kenntnis der antifermentativen, lytischen, und agglu-
tinierenden Wirkungen des Blutserums und der Lymphe," Zbl . Bakt . 27:357,
1900.
31. Landsteiner, K. and Levine, P., "Further Observations on Individual
Differences of Human Blood," Proc. Soc . Exp. Biol. Med. 24 (No. 9):939,
1927.
15-69
REFERENCES (Continued)
32. Landsteiner, K. and Levine, P., "A New Agglutinable Factor Differentiating
Human Bloods," Proc . Soc . Exp. Biol. Med. 24:600, 1927.
33. Landsteiner, K. and Wiener, A., "An Agglutinable Factor in Human Blood
Recognized by Immune Sera Rhesus Blood," Proc. Soc. Exp. Biol. Med.
43:223, 1940.
34. Levine, P., "The Influence of the ABO System on Rh Hemolytic Disease,"
Hum. Biol. 30:14, 1958.
35. Levine, P., Katzin, E. , et al., "Isoimmunization in Pregnancy: Its Possible
Bearing on the Etiology of Erythroblastosis Fetalis," JAMA 116:825, 1941.
36. Levine, P. and Stetson, R. , "An Unusual Case of Intragroup Agglutination,"
JAMA 113:126, 1939.
37. Levine, P., "Serological Factors as Probable Causes of Abortion," J. Hered.
34:71, 1943a.
38. Liley, A.W. , "Intrauterine Transfusion of the Foetus in Haemolytic Disease,"
Brit. Med. J. 2:1107, 1963.
39. Lucey, J.F., Ferreird, M. , et al., "Prevention of Hyperbilirxibinemia of
Prematurity by Phototherapy," Pediatrics 41:1047, 1968.
40. Mengert, W.F., Rights, G.S., et al., "Placental Transmission of Erythrocytes,"
Amer. J. Obstet. Gynec. 69:678, 1955.
41. Smith, T. , "Active Immunity Produced by So-Called Balanced or Neutral Mixtures
of Diphtheria Toxin and Antitoxin," J. Exp. Med. Biol. 11:241, 1909.
42. Stern, K. , Davidsohn, M.D., et al., "Experimental Studies on Rh Immunization,"
Amer. J. Clin. Pathol. 26:833, 1956.
43. Vanden Bergh, A.A.H. and Muller, P., "Uber eine Direkte und Indirekte Dia-
zoreaktion auf Bilirubin," Biochem. Z. 11 ■.'^0 , 1916.
44. Vaughn, V.C., Allen, F.H., Jr., et al., "Erythroblastosis Fetalis: Further
Observation on Kernicterus , " Pediatrics 6:706, 1950.
45. Wara, D.W. , Golbus, M.S., et al . , "Fetal Thymus Glands Obtained from Prosta-
glandin-Induced Abortions: Cellular Immune Function In Vitro and Evidence
of In Vivo Thymocyte Activity Following Transplantation," Transplantation
13:387, 1974.
46. Weech, A.A. , "Genesis of Physiologic Hyperbilirubinemia," Advances in
Pediatrics 2:346, 1947.
REFERENCES (Continued)
47. Weiner, W. , Child, R.M. , et al., "Foetal Cells in the Maternal Circulation
During Pregnancy," Brit. Med. J. 2:770, 1958.
48. Wiener, A.S., "The Use of Heparin When Performing Exchange Transfusions in
Newborn Infants," J. La. Clin. Med. 31:1016, 1945.
49. Wiener, A.S. and Peters, H.R., "Hemolytic Reactions Following Transfusions
of Blood of the Homologous Group with Three Cases in Which the Same
Agglutinogen was Responsible," Ann. Intern. Med. 13:2306, 1940.
50. Working Party on the Use of Anti-D-Immunoglobulin for the Prevention of
Isoimmxinization of Rh-Negative Women During Pregnancy, "Controlled Trial
of Various Anti-D Dosages in Suppression of Rh Sensitization Following
Pregnancy. Report to the Medical Research Council," Brit. Med. J.
2 (No. 910) :75, 1974.
51. Yllpo. A., "Icterus Neonatorum (inkl. I.n. gravis) und Gallenfarbstof fsekre-
tion beim Fotus und Neugeborenen, " Z. Kinderheilk. 9:208, 1913.
52. Zimmerman, D.R., Rh. The Intimate History of a Disease and Its Conquest,
New York: Macmillan Publishing Co., Inc., 1973.
Principals Interviewed
Dr. Louis K. Diamond
Department of Pediatrics
University of California
San Francisco, California
Dr. Julius Krevans
Dean of Medical School
University of California
San Francisco Medical School
San Francisco, California
Dr. Michael Heymann
Cardiovascular Research Institute
and Department of Pediatrics
University of California
San Francisco, California
15-71
u. <
O -I
^ O
I- C LU
LU LU U.
2<
CH
O UJ
Su-
gC >. U. £0
< 2 CO I
St <t
<< X HI >
O O Qifi
_l 1 ! I
J I
X 2 2
J 3 2<
2g
sf
s-S
2 [^
-SJ
(tZ
Ssaz
= 52
iSil ,
six
CHARACTERIZATION
OF HEMOLYTIC
DISEASE OF THE NEWBORN
(ERYTHROBLASTOSIS FETALIS)
ETIOLOGY OF
ERYTHROBLASTOSIS
FETALIS
PROPHYLAXIS
; t"ab"'at. n "**
N/HN
LHF/HN
LHF
" H/A
Tieoo.ES. LHF
LHF
-iZ"
CODES
HUMAN NEONATE
HUMAN
LIVING HUMAN FETUS
(INCLUDING MOTHER)
NONLIVING NEONATE OR
SPONTANEOUS ABORTION
(AUTOPSY)
ANIMAL
Figure 3. Historiograph — Isoimmunization
RESPIRATORY DISTRESS SYNDROME (RDS)
Medical Significance
Respiratory distress syndrome is a major cause of neonatal mortality and
thus represents an important threat to a prematurely born infant. The condition
as it is now recognized is a consequence of lack of sufficient pulmonary develop-
ment in a prematurely born infant. Ninety- five percent of infants who die of
RDS are premature. The overall incidence of RDS has been estimated by several
different methods. In the most recent figures, it was estimated that during the
years 1968 to 1970, the national incidence of RDS was 40,000 cases per year.^°-'
A direct relationship is indicated between the frequency of RDS and the degree
of prematurity, irrespective of whether estimated gestational age or birth weight
is employed as a measure of prematurity.'^ Frequencies as high as 80 percent are
reported in the 1000 to 1250-gram group.
A very large variation in mortality rate from RDS has been reported in the
literature depending upon risk factors and the methods of management. A summary
of deaths in 1969^°° estimated that 1,000 infants per week born in the United States
developed RDS and of this number, approximately 500 died. This would correspond
to an annual mortality of 26,000 infants. The frequency of fatalities obtained
from small populations of randomly selected cases have ranged from 20 to 95 per-
cent .^''*^ A general clinical impression is that disease severity is strongly
influenced by the degree of prematurity, and is corroborated by correlations of
gestational age with mortality.^* Other estimates of national mortality also
show a range from 12,000 to 40,000 cases per year.^'^° In a compilation of deaths
attributed to hyaline membrane disease in 1968, a total of 10,097 deaths were
tabulated. If the incidence of RDS is 40,000 cases per year, this suggests an
overall mortality rate of 28 percent in this country.
The majority of deaths from RDS occur in the first 72 to 96 hours after
birth. The fatality rate for RDS declines nearly exponentially between the first
and fourth 24-hour periods. ^°i The typical clinical characterization of the RDS
infant follows a progressive deterioration in the first 24 to 48 hours accompa-
nied by a high mortality rate during this period. Infants who survive begin to
recover from 72 hours onward. Of these survivors, a certain percentage will
experience morbid sequelae, the two most important of which are neurologic impair-
ment and chronic lunq disease. In the past, data have indicated a rather high
rate (20-27 percent) of secondary neurologic abnormalities resulting from FJDS.^s
Because of recent advances in therapy and management of RDS infants, there is
indication that neurologic sequela may be reduced. ■^
In addition to prematurity, two other risk factors have been shown to lead
to or aggravate the incidence of RDS. These are cesarean section and perinatal
asphyxia. Usher and his co-workers ^^'^^ reviewed histories of over 10,000 vagi-
nally delivered infants and 1,500 cesarean sections. They concluded that the
procedure itself was the responsible factor in the higher incidence of RDS in
the later group. This conclusion was in opposition to an earlier opinion^o that
15-75
elective cesarean section in uncomplicated pregnancies did not lead to a higher
incidence of RDS. The association of RDS with cesarean section was attributed
to a history of maternal hemorrhage rather than to the procedure itself. How-
ever, several of the facts summoned by Usher and others indicate that cesarean
section of itself is a predisposing factor to RDS. A comparison of 1,780 vagi-
nal versus 334 abdominal deliveries performed at 35 to 38 weeks showed an eight-
fold greater incidence of RDS in the abdominally delivered infants.'-' The inci-
dence of RDS in emergency and elective cesarean sections is about the same when
the two infants are compared at equal gestational age. The reason for the predis-
position by cesarean section to RDS is not well understood, although a clue may
be offered by the work of Fedrick and Butler 32 who found that infants delivered
by cesarean section before initiation of labor had a 4-fold higher incidence of
fatal RDS than those delivered by cesarean section during labor. It would thus
appear that the onset of labor in some way prepares the infant's pulmonary system.
Another predisposing factor to the incidence of fatal RDS is the sex of the
neonate. Ratios of the number of males to females who die with hyaline membrane
disease range from 1.4 to 2.0.8^ In a recent study, a ratio of 1.7 was reported.
The suggestion was made that the lungs of females mature at a faster rate than the
lungs of males before birth. However, the higher death rate among the males may
be attributable to the fact that males outnumber females in virtually all dis-
orders leading to death in the neonatal period.'^ The ratio in neonatal mortality
from all causes is from 1.62 to 1.76 for the period 1968 through 1970.^°^
Another factor which has long been implicated in predisposing the neonate
to RDS is maternal diabetes. Several studies indicate that infants from diabetic
mothers definitely do have a higher incidence of SDS. Ranges of 26 to 37 percent
incidence have been reported. ^^'^^'^^'^i'^' However, it is difficult to assess the
effect of maternal diabetes independently because of the very high incidence of
cesarean section and premature births occurring in diabetic mothers. For example,
in Hubbell's study, ^^ cesarean sections were performed in 70 percent diabetic
pregnancies. A subsequent study by Usher ®^ indicates an almost equal incidence
of RDS in infants delivered by cesarean section from diabetic and nondiabetic
mothers when the results are compared according to gestational age. He thus
attributes the high incidence of RDS in infants from diabetic mothers to the
cesarean section procedure rather than to the diabetic condition of the mother.
Irrespective of whether diabetes per se or the higher rate of cesarean section is
the primary factor in the high incidence of RDS in infants from diabetic mothers,
the fact remains that infants from diabetic mothers do have a higher incidence of
RDS. A number of other factors have been associated with the occurrence of RDS in
neonates which are thought to reduce the risk. For example, premature rupture of
the membranes ,82 heroin addiction in the mother, and two or more prior lonsuccess-
ful pregnancies 78 have all been associated with reduced risk of RDS in neonates.
In conclusion, the above facts establish that RDS is a major cause of death
among neonates and that significant morbidity can result in survivors of this
condition.
15-76
Historical Account
The first recorded clinical observation of the hyaline membrane associated
with RDS was reported in 1903 by Hochheim.52 Hochheim reported the existence of
a peculiar membrane which stained blue with hematoxylin which he termed myelin.
Hochheim believed that this myelin was formed from desquamating cells of the
alveolar epithelium. This myelin membrane was subsequently described in the
lungs of newborn children by several German pathologists.* The first descrip-
tion of the hyaline lesion in the English literature was in 1923 by Johnson, ^^
who associated the hyaline membrane with pneiimonia in newborn infants. Hochheim
originally postulated that the origin of the hyaline membrane could be from
amniotic fluid aspirated by the infant. This hypothesis was given further cre-
dence by Farber in 1931,^7 who showed that constituents of amniotic fluid could
be found in neonatal lungs. Aspiration of amniotic fluid continued to be the
most frequently hypothesized etiology for a period of almost 50 years after
Hochheim' s first report. In a summary of cases in the literature of 1903-1952
presented by Tra-Dinh-De ,92 26 studies of hyaline-like membranes are reported.
Of these, 24 ascribed the membrane to aspiration of amniotic fluid. Other etiol-
ogies are also suggested, and these include developmental or congenital abnor-
malities, degeneration of alveolar epithelium, oxygen poisoning, and intrauterine
injury. Gluck suggests in a recent article''^ that at least 50 etiologies were
proposed during the first 50 years after the syndrome was recognized. These
studies seemed to focus particular attention on the hyaline membrane, describing
it as a distinctive coating of the alveoli by an irregular layer of homogeneous
eosinophilic material. In a paper in 1950 by Potter, si atelectasis of a newborn
is divided into two categories, the first being those who die before respiration
and the second, those who die after initial respiration. She also pointed out
that the most important entity which causes hyaline membrane disease is prema-
turity. A detailed study of a large number of newborns in 1950 ''^ resulted in an
excellent description of the clinical abnormalities associated with the formation
of hyaline membrane disease.
In 1953, an important milestone in the diagnosis and, to some extent in the
understanding, of the hyaline membrane was presented by Donald,^* who described a
reticulogranular pattern associated with neonatal atelectasis which appeared on
radiographs. A very significant paper on understanding the etiology of RDS
appeared in 1955 by Gitlin and Craig. *^ These authors showed that the lesions
associated with RDS in the lung contained large amounts of fibrin. Since fibrin-
ogen is not a constituent of amniotic fluid, its origin must lie within the
infant itself rather than from aspirated amniotic fluid. The substantiation of
these findings discounted the hypothesis of aspiration of amniotic fluid as
leading to the formation of a hyaline membrane.
A major advance in understanding the etiology of RDS came in 1959 with the
report of Avery and Mead^ on the surface properties of lung extracts from infants
with hyaline membrane disease. The surface tension properties of extracts from
lungs of premature stillborns, live-born prematures, infants dying from hyaline
*In more recent literature, the term "myelin" has been replaced by the word
"hyaline. "
membrane disease, normal children, and adults were measured and compared. The
results showed that a surface-active substance was found in large amounts in
the lungs of infants over 1200 grams, in children, and in adults. In lung
extracts of very small premature infants and infants dying with hyaline membrane
disease, the surface-active material is deficient. Based on these findings, the
authors suggested a pathogenesis of the disease which is still the basis of the
current understanding. They suggested that the absence of the surfactant lining
in the alveoli resulted in a higher surface tension and predisposed alveolar
collapse after the first breath. This, in turn, would lead to a higher intra-
plural pressure at inspiration resulting in a higher intrathoracic blood volume.
This could then account for the transudation of plasma proteins, which has been
shown to exist in hyaline membrane disease. Thus, the presence of the hyaline
membrane was postulated as being a secondary effect. The primary effect was
atelectasis resulting from collapse of pulmonary alveoli. A subsequent paperso
from this same group showed that excised lungs from infants who died from RDS
had a greatly reduced compliance compared to lungs from stillborn infants and
newborn infants dying from other causes. This low compliance was attributed to
a reduction in the number of units participating in ventilation which, in turn,
could result from collapse of alveoli.
Thus, at this juncture, attention was turned to the role of surfactant in
the etiology of the respiratory distress syndrome. To understand the role of
surfactant, one must go back to a paper published in 1929 by von Neergaard.^^
Von Neergaard reported that the pressure/volume curves obtained by inflating and
deflating lungs with air were not the same as those obtained from inflating and
deflating with an aqueous solution. He postulated that the discrepancies in
pressure necessary to extend the lung with air compared to water and the failure
of the air-inflated lung to deflate along its own curve of expansion were due to
surface tension forces in the lung. By quantifying the differences between the
air and liquid volume/pressure curves, he concluded that approximately 2/3 to
3/4 of the retractive pressure of the liong was due to surface forces. He also
postulated that a surface-active material must be present in the lung to account
for these differences. Between the period of 1929 and 1955, a number of authors
discussed the theoretical importance of the surface properties of the lung. How-
ever, no direct experimental evidence of surface properties in maintaining alveo-
lar stability was obtained until 1955. In that year, Pattle^^ showed that foams
taken from the inner spaces of edetamous lungs contained a potent surface-active
material. Foam was obtained from lungs by producing acute pulmonary edema in
animals and by washing lungs both in vivo and in vitro with a saline solution.
The high stability and nearly constant size of the bubbles in the foam indicated
to Pattle that they must have a very low surface tension. He suggested that the
surface-active material was some form of mucous which was secreted by the lung.
This suggestion originated from earlier work by Macklin,68 who stated that the
Type II pneumonocytes (alveolar cells which constitute from 2 to 10 percent of
the normal alveolar epithelial cells) contained granules which secreted a sub-
stance covering the air surfaces of alveolar cells. He did not at this time,
however, identify this secreted substance as a phospholipid surfactant.
The next important advance in the understanding of the role of lung sur-
factant came in 1957 with the report of Clements. ^^ Using saline extracts from
rat, cat, and dog lungs, the author showed on a Langmuir-Wilhelmy surface balance
15-78
that the surface tension was dependent upon the surface area. The tension varied
from 46 to 10 dynes/cm as the surface area was decreased. He thus demonstrated
hysteresis characteristics similar to the pressure/volume relationship found on
the inflation and deflation of experimental lung samples. In a subsequent paper,
Clements and co-workers i^ began to develop a theoretical basis for the function
of surfactant in lung alveoli. He showed that since the surface tension of the
lung surface decreased as the surface contracted, the alveoli would be stabilized
at low volumes.
Following the classic work of Avery mentioned above, ^ investigations con-
tinued on the relationship of the surfactant to the properties of lung tissue.
In 1951, Clements and co-workers^^ compared the pressure/volume relationships
of human and rat Ivings to the surface-active properties of extracts prepared
from the specimens. The pressure/volume curves and the surface activity of the
extracts showed wide variation among individual samples and yet a high correla-
tion between these two properties was observed. The findings supported the hypoth-
esis that the stability of the pulmonary alveolar structure was dependent upon
the intrinsic surface-active material. The stabilizing activity present in lungs
of newborn infants with hyaline membrane formation was apparently insufficient to
stabilize units smaller than 90 microns in radius at a pressure of 5 cm of water.
On the other hand, even the smallest units of normal lungs could be stabilized at
this pressure. These findings were further corroborated in a subsequent paper
by Gruenwald,5i who made pressure/volume measurements on postmortem lung speci-
mens from 37 infants, and in addition, measured surface activity of saline
extracts. A good correlation was found between the alveolar stability of the
lungs and the surface activity of the extracts.
In line with these findings, the composition of the surface-active material
was being investigated. Klaus and co-workers ^^ analyzed foam obtained from beef
lung and found it contained from 50 to 75 percent lipids and 5 percent nitrogen.
The lipids were composed of 74 percent phospholipids and this portion of the
lipid fraction produced the major effect on reducing surface tension. A number
of subsequent studies indicated that the primary component of the phospholipids
was dipalmitoyl lecithin. Interestingly enough, the presence of high amounts of
this substance had been reported several years earlier by Thannhauser.^° The
physiologic significance of dipalmitoyl lecithin was not known at the time of
this finding, however.
Subsequent to this, a great deal of work has been conducted up to the
present time on the composition and properties of pulmonary surfactant.^® In
a recent summary, Clements reports that surface-active material derived from
lungs contains 41 percent dipalmitoyl lecithin, 25 percent monoenoic lecithin,
9 percent protein, and 1 percent sphingomyelin, with the remainder consisting
of a variety of lipids and phospholipids. The protein portion of the surface-
active material is reproducible in extracts from several animals. This protein
is believed to play an important role in the properties of lung surfactant in
that it has been shown to increase the rate of adsorption of phospholipids on the
surface. Lecithin by itself would be ineffective at the surface of the alveoli,
although it is the principal component of the surface-active material which is
largely responsible for the stability of the alveoli. Clements points out that
a turnover of phospholipids at the alveolar surface occurs as the film collapses.
Therefore, the lung must continuously supply phospholipids to maintain stability.
In the absence of an active synthesis of phospholipids, an infant's lung might
be stable for a short period of time and subsequently degenerate because the
rate of synthesis could not keep up with the phospholipid turnover.
In parallel with the studies of phospholipid composition, research efforts
were directed to the methods of synthesis of phospholipids by the lung tissue.
As mentioned previously, Macklin suggested the Type II alveolar cells were secre-
tory. This work was followed up in 1961 by Klaus and co-workers ,^9 who proposed
that the surface-active lining of the mammalian lungs forms in the mitochondria
of the Type II alveolar cells. In conjunction with this, Buckingham and Avery
reported^^ that the surface activity of extracts from mice lungs show very little
surfactant activity until the nineteenth day. The appearance of the surfactant
activity corresponds with the appearance of the inclusion bodies in the Type II
alveolar epithelial cells. Thus, this work, as well as that of many others,
showed the correlation between appearance of the Type II cells and the surfactant
activity. A great deal of experimental work then followed on the development of
surface activity in mammalian lungs. "S-*'* These studies identified two main path-
ways of lecithin synthesis. The first, called the CDP choline pathway, was shown
to be the major pathway in the rabbit and sheep fetus. The second pathway
involves methylation of phosphatidyl ethanolamine. In the sheep and rabbit, this
second pathway, designated the methylation pathway, is not significant until sev-
eral days after birth. The story, however, is different in the monkey and human
fetus, as shown by the studies of Gluck and co-workers."^ In vitro studies on
nonviable human fetuses demonstrated that the CDP choline pathway could be iden-
tified by 18 to 20 weeks' gestation. However, it was relatively inactive until
the thirty-sixth week of gestation. The methylation reaction was identifiable
by the twenty-fourth week of gestation but was evidenced only at a very low activ-
ity. Thus, the animal models which were studied intensively to elucidate the
mechanisms of phospholipid synthesis had some differences when compared to the
human. Following Gluck' s work, a series of studies on the enzymes involved in
the synthesis of lecithin in humans was performed by Zachman.^"^ The details of
the biosynthetic pathway are too numerous to be described in detail in this
review. Suffice it to say that work with human tissue was essential to establish
the biosynthetic pathway by which lecithin is synthesized in the human lungs. A
recent report by Gluck and co-workers indicates that the rhesus monkey may serve
as a good model for studying development of phospholipid synthesis ."^
With the establishment that lecithin was synthesized by lurig tissue and was
the major component of the surfactant, the question arose as to how one could use
this knowledge in the prediction of respiratory distress syndrome. An important
step in this direction came in 1957 with the work of Scarpelli,^^ who showed that
the lung was the source of tracheal fluid phospholipids. He demonstrated that
the phospholipid content of tracheal fluid was similar to that of amniotic fluid
and suggested that the former might be a source of phospholipids in the amniotic
fluid. Demonstration of the validity of this concept was made in the classic
work of Gluck in 1971 ,*5 who showed that changes in phospholipids in amniotic
fluid obtained by amniocentesis reflected those in the lung of the developing
fetus. A sudden increase in the concentration of lecithin occurs at 35 weeks and
this increase signifies the maturity of the pulmonary alveolar lining. The esti-
mation of the lecithin concentrations was based upon the fact that the amniotic
fluid sphingomyelin concentration remained relatively constant throughout gesta-
tion and could serve as an internal standard. These results implied that the
likelihood of RDS could be diagnosed antenatally by measurement of the lecithin/
sphingomyelin ratio in amniotic fluid. In the ensuing four years after Gluck's
study, over a hundred reports have appeared in the literature.^ These reports
have confirmed the clinical predictability of amniotic fluid phospholipids for
the risk of RDS. A compendium of the results indicates that a properly deter-
mined amniotic fluid L/S ratio greater than 2.0 indicates with almost 100 percent
probability that the infant will not develop RDS. The question remains open,
however, about the probability of RDS occurring in L/S ratios less than 2.0.
Another method of determining surfactant activity of amniotic fluid is the shake
test described by Clements .i^ a number of studies have been conducted on the
value of this test in predicting the pulmonary maturity of an infant, and these
indicate that this method can provide a good screening method. If the shake test
is positive, there is a very high probability of pulmonary maturity. If the test,
however, is negative, it is advisable to obtain an L/S ratio to determine more
accurately the degree of fetal maturity.
The knowledge that a lack of sufficient surfactant synthesis led to RDS,
coupled with the ability to predict pulmonary maturity by amniocentesis led to
the desire to find a method of stimulation of fetal lungs antenatally in cases
where premature delivery was a threat. Such an advance came in 1972 in work by
Liggins and Howie .6^ These authors showed that the administration of glucocorti-
coids more than 24 hours before delivery decreased the likelihood of postnatal
respiratory distress.
To understand the rationale for this work, it is necessary to review
briefly past work on the effect of steroids on fetal stimulation. As early as
1953, Moog^3 had demonstrated that cortisone induced certain enzymes in the
intestines of fetal mice. In 1961, Migeon et al.,^° had shown that Cortisol
administered to mothers at midpregnancy could cross the placenta from mother to
fetus. Because of the increasing use of cortisone in medical practice for con-
ditions such as severe asthma, rheumatoid arthritis, and Rh sensitization, sev-
eral studies were performed during this period and later to determine the danger
or safety of administering cortisone during pregnancy . 69.97, 102 Although caution
was advised, this therapy did not appear to have an untoward effect on the infant,
and long-term corticosteroid therapy was not felt to be a contraindication to
pregnancy. : j-.-/
However, it was not until 1968 that the role of hormonal steroids in fetal
lung maturation was suspected. Buckingham et al.,'^^ were the first to suggest
that fetal steroids may influence pulmonary epithelial cell maturation, just as
Moog had found in the fetal intestine. The same year, Liggins^^ in New Zealand
reported that infusions of Cortisol into fetal lambs resulted in premature par-
turition. This was followed by a second report by Liggins^s in 1969 that dexa-
methasone caused the same effect. More important, however, was his finding that
dexamethasone administered directly to fetal lambs promoted lung maturation as
determined by physiological parameters. He suggested that this may be the result
of accelerated appearance of surfactant activity. It is also important to note
that Liggins found that neither Cortisol or dexamethasone induced parturition
when administered to the pregnant ewe rather than directly to the fetus.
15-81
Dr. Mary Ellen Avery, while visiting with Dr. Liggins in New Zealand,
quickly recognized the significance of his findings and initiated an intensive
research program at McGill University-Montreal Children's Hospital Research
Institute. By 1969, DeLemos et al. ,2^ reported preliminary findings which con-
firmed the accelerated maturation effects of corticoids and ACTH in fetal lambs,
and in 1970, DeLemos et al.,22 were the first to demonstrate increased surfactant
in the lungs of cortisol-treated fetal lambs. This classical report set off what
amounted to an explosion in research into the role of steroidal hormones in fetal
lung maturation. The effect of corticoids on general fetal liong maturation was
quickly confirmed in lambs, rabbits, and rats ,57.6i,62,63,74,8o and the effect on
increased surfactant was confirmed in rabbits .^^'^^'^^
In 1971, Kotas and Avery ^^ suggested that the administration of a glucocor-
ticoid accelerated a normal sequence of differentiation in the fetal rabbit lung.
This was quickly followed by a report by Wang et al.,98 who observed that the
Type II cells of cortisol-injected rabbit fetuses underwent rapid cytodif feren-
tiation showing decreased quantities of glycogen and increased numbers of lamellar
granules. The same effect was reported by other laboratories in the same year. 5^'^°
Also in 1971, Naeye et al.,'^ reported that anencephalic neonates with hypoplastic
adrenal cortices had, in comparision with neonates without this malformation, less
than half the mass of osmiophilic granules in Type II alveolar cells.
As a result of these key discoveries in the 1968-1971 period, several fronts
were opened for further investigation. As would be expected, several laboratories
began to probe deeper into the basic questions of pneumonocyte enzyme induction by
steroidal hormones and glucocorticoid receptors in the fetal lung. Farrell and
Zachman,2''^° for example, reported in 1972 and 1973 that there was a marked
enhancement of choline incorporation into surface-active lecithin in fetal rabbit
lung after pretreatment with dexamethasone, and in 1973, Farrell and Blackbum-^^
demonstrated an increase in choline phosphotransferase and lecithin synthesis in
rat lungs from decapitated fetuses six hours after intraperitoneal injection of
dexamethasone. Smith and co-workers extended these studies into cell cultures
prepared from fetal rabbit lungs and midterm human fetal lung.^^'^^ Their studies
suggest that Cortisol may increase fetal pulmonary cellular growth in early ges-
tation while enhancing maturation and slowing growth as term approaches. During
this same period, Ballard and Ballard demonstrated first in rabbitsi° and then in
the human fetus and neonate^i that the lung contains the receptor mechanism neces-
sary for direct responsiveness to glucocorticoids. In a series of papers,
Giannopoulos and co-workers -^^-ai demonstrated large variations in the levels of
lung glucocorticoid-binding protein (GBP) among different species as well as in
the same species at different developmental stages.
While several other workers continued to demonstrate the role of steroidal
hormones in regulating surfactant synthesis in animal models such as the lamb,
rat, and monkey ,80'3 1.23 Liggins and Howie^^ in 1972 published the preliminary
results of a controlled clinical trial in New Zealand. They reported that ante-
partum glucocorticoid treatment reduced the incidence of RDS in human infants
born before 32 weeks of pregnancy. The same year, Baden and co-workers ^ in
Montreal reported on a clinical trial of hydrocortisone therapy in neonates with
RDS. They found no endogenous deficiency of corticosteroids in infants with RDS
and demonstrated that the postnatal use of corticosteroids did not benefit the
infant with RDS. The following year, Howie and Liggins*^ reported on an extended
clinical trial with antepartum betamethasone treatment. Reduced incidence of RDS
was confirmed for infants born before 32 weeks of pregnancy and more than one day
but less than seven days after the start of treatment. They cautioned that intra-
partum fetal deaths were greater in the treated group than in controls in those
patients with evidence of placental damage. While this difference was not at a
significant level, preeclampsia would contraindicate betamethasone administration.
The following year, Fargier and co-workers^s in France reported on a similar clini-
cal trial using betamethasone. They reported that the antepartum treatment reduced
the incidence of hyaline membrane disease in premature infants from 20 percent in
the control group to 4.4 percent in the infants born of treated mothers.
The significance of th'e findings of Bader et al. ,^8 who had reported that
RDS infants had no endogenous deficiency of corticosteroids, was clarified by
Murphy ^^ in 1974, who demonstrated that the Cortisol and cortisone levels in mixed
cord blood, taken at delivery, was lower in infants which subsequently developed
RDS than in normal infants. She suggested that pre- and postnatal stress increased
Cortisol levels; therefore, the stress associated with the RDS would quickly lead
to a rise in Cortisol in the distressed infant and the Cortisol deficiency present
at birth would be undetected in subsequent measurements.
In 1973, Spellacy et al.,^^ reported that the rate of rise of amnionic-
fluid L/S ratio in human pregnancies was significantly increased by the adminis-
tration of a synthetic glucocorticoid to the mother. Similar findings were
reported by Caspi et al.,-'* the same year. While these studies were limited in
scope and the significance of the findings needs to be carefully evaluated, they
do illustrate the first use of amniocentesis in the steroid investigations. In
January, 1975, Fencl and Tulchinsky^s reported on a study relating total Cortisol
concentration in amniotic fluid with the L/S ratio at various stages of gestation
in normal human pregnancy. They found a good rank correlation between Cortisol
and L/S ratio with a sharp increase in total amniotic-fluid Cortisol after the
thirty-fourth week of gestation which continued to rise as pregnancy progressed.
They also noted that no occurrence of RDS was observed in the newborns when,
48 hours before labor, total amniotic-fluid Cortisol was higher than 50 mg. per
milliliter.
While the role of surfactants has occupied a central place in the last
several years in the etiology and prenatal treatment of RDS, a number of other
lines of investigation also shed some light on the other aspects of fetal devel-
opment. One of these concerns the role of proteolytic enzyme inhibitors in the
maturation of the lung. In 1970, it was first reported by Evans and co-workers^*
that a correlation existed between the incidence of RDS and reduced alpha-1 anti-
trypsin levels. This result was confirmed in a subsequent paper ^^ in which the
same authors reported that total trypsin inhibitory capacity levels were signifi-
cantly lower in the umbilical cord serum of newborn infants with RDS than in
weight-matched control subjects. These results suggested that serum enzyme
inhibitor levels could be of diagnostic value in the newborns for predicting the
susceptability to RDS. The possibility of an antenatal diagnosis was also inves-
tigated by performing amniocentesis in 30 women in whom saline-induced abortions
of presumably normal fetuses were to be performed. These were obtained at 12-22
weeks gestation and some relationship was found between alpha-1 antitrypsin levels
and the gestational age. Further studies on this phenomenon^" were performed by
examining the lungs of 20 newborn infants whose death was attributed to RDS.
Eight of the ten infants who had hyaline membranes also had alpha-1 antitrypsin
present in the lungs. This protein was not detected in infants who did not have
hyaline membrane. The authors suggested that alpha-1 antitrypsin may play a role
in the formation of hyaline membrane. The association of serum trypsin inhibitor
capacity and RDS was independently confirmed by Kotas and co-workers.** The
trypsin inhibitory capacity of umbilical cord serum was measured in 112 premature
and 164 full-term infants to predict the subsequent development of fatal RDS.
The activity of the trypsin inhibitor rose with weight in infants weighing between
1500-2500 grams. These authors concluded that umbilical cord trypsin inhibitory
capacity measurement may be a useful test to identify newborn premature infants
who are likely to develop fatal RDS. This finding, however, has been disputed
recently by Francis and co-workers,''^ who stated they found no relationship
between antitrypsin levies in infants with RDS. They felt the trypsin inhibitor
levels were indicative of fetal development in general and were not specific
indicators of RDS.
Another possible aspect of the etiology of RDS is the effect of the fibri-
nolytic system. As indicated previously, a major component of the hyaline mem-
brane is fibrin which is formed from transudation of plasma proteins into the
alveolar spaces. In 1963, Ambrus and co-workers^ reported that the serum of pre-
mature infants had little or no plasminogen and associated this lack with the
pathogenesis of RDS. They explored the therapeutic value of administering uro-
kinase-activated hiiman plasmin in cases of RDS . ^ A substantial increase in the
survival rate was noted, however, because of the high cost of urokinase, practical
application of this result remained somewhat questionable. An alternative to
urokinase-activated plasmin is plasminogen itself. A study of the effect of
plasminogen administration was recently reported." A double blind study was per-
formed with 100 premature infants in which plasminogen or placebo was administered
to the infants immediately after birth. The treated infants have a significantly
lower incidence of severe RDS and death resulting from RDS. Thus another possible
mode of prophylaxis of RDS may be indicated by these studies.
One of the most effective methods of therapy for RDS is the application of
continuous distending airway pressure."® The development of this method arose
from the understanding of the lack of stability of the pulmonary alveoli due to
lack of surfactant. By the use of a low continuous pressure at end-aspiration,
the alveoli are, in essence, prevented from collapsing. This form of therapy
results in better gas exchange than does conventional ventilation, and its early
application may have some advantages in altering the course of RDS.
Contribution of Fetal Research to RDS
Fetal research played an important role in several key discoveries in the
understanding of the etiology of RDS. After the classic work of Avery in 1959
in which it was demonstrated that the lung extracts of infants who died from RDS
had very low surfactant levels compared to lungs of premature infants dying from
other causes, the role of the development of the surfactant biosynthesis system
in the lungs assumed a central place in the etiology. The work in 1971 by Gluck
in which he showed that the degree of maturity of the lung surfactant system
could be predicted through amniocentesis was a landmark in the progress made
toward conquering RDS. In Gluck 's subsequent 1972 paper, he showed differences
in the surfactant system of the human fetus compared to animal models. This, in
turn, implied that research in the developing human fetus was essential for fur-
ther understanding of the pulmonary surfactant system.
Prior to the initial clinical trial of antepartum glucocorticoid treatment
conducted in New Zealand by Liggins and Howie, human fetuses had not been used
in research on steroid function in lung maturation. Lambs, rabbits, and rats
had been used to demonstrate the potential value of steroid treatment in acceler-
ating fetal lung maturation. Of course, the early work of Migeon and others who
had investigated the effect of steroidal hormone medication in pregnant women was
very important. All of the animal studies had required direct infusion of the
fetus for effective treatment because the corticosteroids did not cross the animal
placenta. The fact that Migeon et al., had demonstrated that Cortisol and corti-
costeroid did cross the human placenta allowed Liggins and Howie to administer the
drug to the mother, a far less risky procedure. Therefore, the clinical trial in
New Zealand was the first human experimentation directly related to the use of
hormones in reducing the risk of RDS.
As previously discussed, this field of research is in its infancy with many
lifesaving discoveries yet to be made. Hiiman fetal research will be an important
part of these continuing studies since it has already been demonstrated that major
species differences exist. In past years there has been no satisfactory animal
model for the mother-placenta- fetus system for studies aimed at unraveling the
complex hormonal role in fetal lung development, although recent reports indicate
that the rhesus monkey is promising.
Effect of a Retrospective Ban on Fetal Research
As indicated previously, the ability to perform research involving the human
fetus played an important role in understanding the etiology of RDS. The impor-
tant work by Gluck in 1971 in which he followed the appearance of phospholipids in
amniotic fluid was based on analysis of samples obtained by amniocentesis. Had he
not been able to perform amniocentesis, this method for predicting fetal maturity
and the resulting ability of the fetus to survive would not have been developed.
Furthermore, understanding of certain aspects of the maturation processes of the
human fetus would be lacking. As Gluck pointed out, the human is different from
available animal models, and thus an accurate understanding of human fetal matur-
ation processes must be obtained from human studies.
The method of antenatal steroid treatment to stimulate development of the
fetal pulmonary surfactant system was, of necessity, evaluation in a human clini-
cal trial. A large number of animal studies had indicated that administration of
steroids could stimulate lung maturation of the fetus. However, the relevance
and value of this treatment for the human could only be determined by studies in
the human. Admittedly, this treatment is still experimental, and its ultimate
value still open to some questions. But if human studies had not been done,
animal studies related to this would be merely of a laboratory finding reported
in physiological journals.
Future Outlook
Despite the fact that significant advances have been made in understanding
the etiology of respiratory distress syndrome, a great many questions still remain
unanswered. In the broadest sense, a complete understanding of the process of
human fetal development is still lacking. Although a great deal of work has been
done with the development of the pulmonary system in laboratory animal models, the
relevance of these models to the human fetus is not well established. In fact, it
has been shown that the phospholipid biosynthetic pathways in animal models are
different from those in humans. A great deal remains to be learned about the
biochemical messengers that prepare the fetus to survive when birth is imminent.
Stimulation of the phospholipid biosynthetic pathway of the fetus by admin-
istration of glucocorticoids to the mother offers an attractive route for the pro-
phylactic prevention of RDS. However, much remains to be learned about this
before antenatal steroid administration can be considered an acceptable clinical
method. In the first place, the reasons for its lack of effectiveness after
32 weeks gestation need to be determined. Secondly, the effect of glucocorticoids
on other biosynthetic and metabolic pathways in the fetus has not been elucidated.
The report of Liggins and co-workers of a higher intrapartiim death rate in the
treated infants from toxemic mothers as compared to the controls needs to be inves-
tigated further for its statistical significance. Another question which remains
to be answered is the long-term effect of administration of glucocorticoids on the
child. It is possible that a child treated through the mother with glucocorticoids
may have sequelae several years subsequent to birth. As stated above, the bio-
chemical messengers which prepare the fetus for survival in the outside environment
when delivery is imminent are not well understood. A long period of labor appears
to induce maturation in a premature fetus's pulmonary system. It is well estab-
lished that delivery of a premature infant by cesarean section before the onset of
labor results in a much higher risk of RDS. The reasons why the lack of a labor
period causes this predisposition need to be clearly elucidated.
Further work also needs to be done on the efficacy of plasminogen treatments
of infants who have a high risk of KDS. The clinical trials performed thus far
indicate a statistically significant benefit from plasminogen treatments, but
larger numbers of cases need to be done to establish overall efficacy. Since
achieving an understanding of EDS involves an understanding of the overall process
of the human fetal maturation process, further research in this area should have
implications over a very broad range. An understanding of the nature of hormone
receptors and the induction of biosynthetic pathways could be a result of these
investigations. Contributions are likely to be made in understanding of the eti-
ology of such important diseases as emphysema and cancer. An effective armamen-
tarium of treatment methods, both antenatal and postnatal, for RDS can be expected
from the lines of investigation now underway and hopefully can lead to a very
large saving of human life in the future.
REFERENCES
1. Ambrus, CM., et al., "Studies on Hyaline Membrane Disease: Fibrinolysis
System in Pathogenesis and Therapy," Ped. 32:10, 1963.
2. Ambrus, CM., et al., "Studies on Hyaline Membrane Disease. III. Thera-
peutic Trial of Urokinase-Activiated Human Plasmin," Ped. 38:231, 1966.
3. Ambrus, CM., et al. , "Evaluation of Survivors of Respiratory Distress Syn-
drome at Four Years of Age," Amer. J. Dis . Child. 120:296, 1970.
4. Ambrus, CM., et al., "Plasminogen in the Prevention of Hyaline Membrane
Disease," Am. J. Dis. Child. 127:189, 1974.
5. Avery, M.E. and Mead, J., "Surface Properties in Relation to Atelectasis
and Hyaline Membrane Disease," Am. J. Dis. Child. 97:517, 1959.
6. Avery, M.E., The Lung and Its Disorders in the Newborn Infant, Ed. 1,
Philadelphia: W.B. Saunders Co., 1968, p. 111.
7. Avery, M.E., personal communication. o
8. Baden, M. , et al . , "A Controlled Trial of Hydrocortisone Therapy in Infants
with Respiratory Distress Syndrome," Ped. 50:526, 1972.
9. Ballabriga, A., et al., "Respiratory Pathology in the Immediate Postnatal
Period," Acta Paedit. Scand. 59:497, 1970. , . ..
10. Ballard, P.L. and Ballard, R.A., "Glucocorticoid Receptors and the Role of
Glucocorticoids in Fetal Lung Development," Proc. Natl. Acad. Sci. 69:2668,
1972.
11. Ballard, P.L. and Ballard, R.A., "Cytoplasmic Receptor for Glucocorticoids
in Lung of the Human Fetus and Neonate," J. Clin. Invest. 53:477, 1974.
12. Buckingham, S. and Avery, M.E., "Time of Appearance of Lung Surfactant in
the Fetal Mouse," Nature 193:688, 1962.
13. Buckingham, S., et al., "Is Lung an Analog of Moog's Developing Intestine?
I. Phosphatases and Pulmonary Alveolar Differentiation in Fetal Rabbits,"
Fed. Proc. 27:328, 1968.
14. Caspi, E., "Amniotic-Fluid Lecithin/Sphingomyelin Ratios and Dexamethasone, "
Lancet, 2 (No. 828):575, 1973.
15. Clements, J.A. , "Surface Tension of Lung Extracts," Proc. Soc . Exp. Biol.
in Med. 95:170, 1957.
REFERENCES (Continued)
16. Clements, J. A., et al., "Pulmonary Surface Tension and the Mucous Lining
of the Lungs: Some Theoretical Considerations," J. Appl. Physiol. 12:262,
1968.
17. Clements, J. A., et al., "Pulmonary Surface Tension and Alveolar Stability,"
J. Appl. Physiol. 16:444, 1951.
18. Clements, J. A., et al., "Assessment of the Risk of the Respiratory Distress
Syndrome by a Rapid Test for Surfactant in Amniotic Fluid," New Eng. J.
Med. 286:1077, 1972.
19. Clements, J.A. , "Composition and Properties of Pulmonary Surfactant,"
Respiratory Distress Syndrome, C.A. Villee, D.B. Villee, and J. Zuckerman,
editors, New York: Academic Press, 1973, p. 77.
20. Cohen, M.M., "The Relationship of Pulmonary Hyaline Membrane to Certain
Factors in Pregnancy and Delivery," Ped. 26:42, 1960.
21. DeLemos , R.A. , et al., "Induction of Pulmonary Surfactant in the Fetal Lamb
by Hydrocortisone," (abstract), Ped. Res. 3:505, 1969.
22. DeLemos, R.A. , et al., "Acceleration of Appearance of Pulmonary Surfactant
in the Fetal Lamb by Administration of Corticosteroids," Am. Rev. Resp.
Dis. 102:459, 1970.
23. DeLemos, R.A. and McLaughlin, G.W. , "Induction of the Pulmonary Surfactant
in the Fetal Primate by the Intrauterine Administration of Corticosteroids,
Ped. Res. 7:425, 1973.
24. Donald, I. and Stiner, R.E., "Radiography in the Diagnosis of HyaJ ine
Membrane," Lancet 2:846, 1953.
25. Evans, H.E., et al . , "Serum Enzyme Inhibitor Concentrations in the Respira-
tory Distress Syndrome," Am. Rev. Resp. Dis. 101:359, 1970.
26. Evans, H.E., et al . , "Serum Trypsin Inhibitory Capacity and the lodiopathic
Respiratory Distress Syndrome," J. Ped. 81 (No. 3):588, 1972.
27. Farber, S. and Sweet, I.K., "Amniotic Sac Contents in the Lungs of Infants,"
Am. J. Dis. Child. 4242:1372, 1931.
28. Fargier, P., et al . , "Prevention of the Respiratory Distress Syndrome of
the Newborn. Value of Antepartum Treatment with Glucocorticoids," iVouv.
Presse. Med. 3 (No. 25):1595, 1974.
29. Farrell, P.M. and Zachman, R.D. , "Enhancement of Lecithin Synthesis and
Phosphorylcholine Glyceride Transferase Activity in the Fetal Rabbit Lung
After Corticosteriod Administration," Ped. Res. 6:337, 1972.
REFERENCES (Continued)
30. Farrell, P.M. and Zachman, R.D., "Induction of Choline Phosphotransferase
and Lecithin Synthesis in the Fetal Lung by Corticosteroids," Science
179:297, 1973.
31. Farrell, P.M. and Blackburn, W.R. , "Cortisol and Lung Choloine Phosphotrans-
ferase (CPT) Activity in the Fetal Rat After In Utero Decapitation," Ped.
Res. 7:308, 1973.
32. Fedrick, J. and Butler, N.R. , "Hyaline Membrane Disease," Lancet 2:758, 1972.
33. Fencl, M. and Tulchinsky, D. , "Total Cortisol in Amniotic Fluid and Fetal
Lung Maturation," New Eng. J. Med. 292 (No 3):133, 1975.
34. Fierer, J.A. , et al., "Alpha-1 Antitrypsin in the Lungs of Newborn Infants
with Respiratory Distress Syndrome," J. Ped. 85:698, 1974.
35. Fisch, R.O., et al. , "Neurological Status of Survivors on Neonatal Respira-
tory Distress Syndrome," J. Ped. 73:393, 1968.
36. Francis, G. , et al. , "Cord Sera Antitrypsin Activity and the Respiratory
Distress Syndrome," Clin. Ped. 13 (No. 7):600, 1974.
37. Gellis, S. and Hsia, D. , "The Infant of the Diabetic Mother," Am. J. Dis.
Child. 97:1, 1959.
38. Giannopoulos, G. , et al., "Cortisol Receptors in Rabbit Fetal Lung," Biochem.
Biophys. Res. Commun. 47:411, 1972.
39. Giannopoulos, G. , "Glucocorticoid Receptors in Lung. I. Specific Binding of
Glucocorticoids to Cytoplasmic Components of Rabbit Fetal Lung," J. Biol.
Chem. 248:3876, 1973.
40. Giannopoulos, G. , "Levels of Glucocorticoid Receptors in Lungs of Various
Species During Development," Fed. Proc. 32:651, abstract, 1973.
41. Giannopoulos, G. , "Variations in the Levels of Cytoplasmic Glucocorticoid
Receptors in Lungs of Various Species at Different Developmental Stages,"
Endocr. 94:450, 1974.
42. Gitlin, D. and Craig, J.M., "The Nature of the Hyaline Membrane in Asphyxia
of the Newborn," Ped. 17:64, 1956.
43. Gluck, L. , et al . , "The Biochemical Development of Surface Activity in
Mammalian Lung," Ped. Res. 1:237, 1967.
44. Gluck, L. , et al. , "The Biochemical Development of the Surface Activity in
Mammalian Lung. Part II," Ped. Res. 1:247, 1967.
45. Gluck, L. , et al., "Diagnosis of the Respiratory Distress Syndrome by
Amniocentesis," Am. J. Ob. Gyn. 109:440, 1971.
15-89
REFERENCES (Continued)
46. Gluck, L. , et al., "Biochemical Development of Surface Activity in Mammalian
Lung. Part IV. Pulmonary Lecithin Synthesis in the Human Fetus and New-
born and Etiology of Respiratory Distress Syndrome," Ped. Res. 5:81, 1972.
47. Gluck, L., "Recognition and Factors Leading to Respiratory Distress Syndrome,
Birth Defects and Fetal Development: Endocrine and Metabolic Factors,
K.S. Morhissi, editor, Springfield: C.C. Thomas, 1974.
48. Gluck, L. , et al., "Comparison of Phospholipid Indicators of Fetal Lung
Maturity in Amniotic Fluid of Monkey (Macaca mulatta) and Baboon (Papio
Papio)," Am. J. Ob. Gyn. 230:524, 1974.
49. Gregory, G.A. , et al . , "Treatment of the Idiopathic Respiratory Distress
Syndrome with Continuous Positive Airway Pressure," New Eng. J. Med.
284:1333, 1971.
50. Gribetz, I., et al., "Static Volume-Pressure Relations of Excised Lungs in
Infants with Hyaline Membrane Disease, Newborn, and Stillborn Infants,"
J. Clin. Invest. 38:2168, 1959.
51. Gruenwald, P., et al., "Correlation of Mechanical Properties of Infant Lungs
with Surface Activity of Extracts," Proc. Soc. Exp. Biol, in Med. 109:369,
1962.
52. Hochheim, K. , "Ueber Einige Befunde in den Lungen von Neugeborenen und die
Beziehung Derselben zur Aspiration von Fruchtwasser, " Centralblatt fur
Path. 14:537, 1903.
53. Howie, R.N. and Liggins, G.C., "Prevention of Respiratory Distress Syndrome
in Premature Infants by Antepartum Glucocorticoid Treatment," in Respira-
tory Distress Syndrome, C.A. Villee, D.B. Villee, and J. Zuckerman,
editors. New York: Academic Press, 1973, p. 369.
54. Hubbell, J. P., Jr., et al., "The Newborn Infant of the Diabetic Mother,"
Med. Clin. N. Amer . 49:1035, 1965.
55. Hubbell, J. P., Jr. and Drorbaugh, J.E., "Infants of Diabetic Mothers: Neo-
natal Problems and Their Management," Diabetes 14:157, 1965.
56. Johnson, W.C., "Pneumonia in Newborn Infants with Lesion Resembling Influ-
enza," Proc. N.y. Path. Soc. 23:138, 1923.
57. Kikkawa, U. , et al., "Morphologic Development of Fetal Rabbit Lung and Its
Acceleration with Cortisol," Am. J. Path. 64:423, 1971.
58. Klaus, M.H., et al., "Composition of Surface-Active Material Isolated from
Beef Lung," Proc. Nat. Acad. Sci . 47:1858, 1961.
15-90
REFERENCES (Continued)
59. Klaus, M.H., et al., "Alveolar Epithelial Cell Mitochondria as Source of
the Surface Active Lung Lining," Science 137:715, 1952.
60. Klaus, M.H., "Pulmonary Diseases of the Newborn," in Pediatrics, H.L. Bamett
and A.H. Einhorn, editors. New York: Appleton-Century-Crofts, 1972,
p. 1261.
61. Knelson, J.H. , "Environmental Influence on Intrauterine Lung Development,"
Arch. Intern. Med. 127:421, 1971.
62. Kotas , R.V. and Avery, M.E., "Accelerated Appearance of Pulmonary Surfactant
in the Fetal Rabbit," J. Appl . Physiol. 30:358, 1971.
63. Kotas, R.V., et al., "Evidence for Independent Regulators of Organ Maturation
in Fetal Rabbits," Ped. 47:57, 1971.
64. Kotas, R.V., et al., "Umbilical Cord Serum Trypsin Capacity and the Idiopathic
Respiratory Distress Syndrome," Ped. 81:593, 1972.
65. Liggins, C.G., "Premature Parturition After Infusion of Corticotropin or
Cortisol into Foetal Lambs," J. Endocr. 42:323, 1968.
66. Liggins, G.C., "Premature Delivery of Foetal Lambs Infused with Glucocorti-
coids," J. Endocr. 45:515, 1969.
67. Liggins, G.C. and Howie, R.N., "A Controlled Trial of Antepartum Glucocorti-
coid Treatment for Prevention of the Respiratory Distress Syndrome in
Premature Infants," Ped. 50:515, 1972.
68. Macklin, C.C., "The Pulmonary Alveolar Mucoid Film and the Pneumonocytes, "
Lancet 266:1099, 1954.
69. Margulis, R.R. and Hodgkinson, C.P., "Evaluation of the Safety of Cortico-
tropin (ACTH) and Cortisone in Pregnancy," Ob. Gyn. 1:276, 1953.
70. Migeon, C.J., et al., "The Transplacental Passage of Various Steroid Hormones
in Mid-Pregnancy," Rec. Prog. Horm. Res. 17:207, 1961.
71. Miller, H.C. and Jennison, M.H. , "Study of Pulmonary Hyaline-Like Material
in 4,117 Consecutive Births: Incidence-Pathogenesis , and Diagnosis,"
Ped. 5:7, 1950.
72. Miller, H.C. and Futrakul , P., "Birth Weight, Gestational Age, and Sex as
Determining Factors in the Incidence of Respiratory Distress Syndrome of
Prematurely Born Infants," J. Ped. 72:628, 1968.
73. Moog, F., "The Influence of the Pituitary-Adrenal System on the Differenti-
ation of Phosphatase in the Duodenum of the Suckling Mouse," J. Exptl .
Zool. 124:329, 1953.
15-91
REFERENCES (Continued)
74. Motoyama, E.K., et al., "Effect of Cortisol on the Maturation of Fetal
Rabbit Lungs," Ped. 48:547, 1971.
75. Murphy, B.E.P., "Cortisol and Cortisone Levels in the Cord Blood at Delivery
of Infants With and Without the Respiratory Distress Syndrome," Am. J.
Ob. Gyn. 119:1112, 1974.
76. Naeye, R. I . , et al., "Neonatal Mortality, the Male Disadvantage," Ped.
48:902, 1971.
77. Naeye, R.L., et al., "Adrenal Gland Structure and the Development of Hyaline
Membrane Disease," Ped. 47:650, 1971.
78. Naeye, R.L. , "Epidemiology of Hyaline Membrane Disease - Selected Aspects,"
in Respiratory Distress Syndrome, C.A. Villee, D.B. Villee, and
J. Zuckerman, editors. New York: Academic Press, 1973.
79. Pattle, R.E., "Properties, Function, and Origin of the Alveolar Lining
Layer," Nature 175:1125, 1955.
80. Platzker, A.C.G., et al . , "Surfactant Appearance and Secretion in Fetal
Lamb Lung in Response to Dexamethasone, " Ped. Res. (abstract), 6:406,
1972.
81. Potter, E.L., "Pathology of Prematurity," Am. Med. Worn. Assoc. 5:391, 1950.
82. Richardson, C.J., et al., "Hyaline and Ruptured - the Membrane' Dilemma,"
Ped. Res. 7:178, 1973.
83. Scarpelli, E.M. , "The Lung Tracheal Fluid and Lipid Metabolism of the
Fetus," Ped. 40:951, 1967.
84. Shanklin, D.R. , "The Sex of Premature Infants with Hyaline Membrane Disease,'
So. Med. J. 56:1018, 1963. ;._ , ■
85. Smith, B.T., et al., "The Growth Promoting Effect of Cortisol on Human Fetal
Lung Cells in Culture," Ped. Res. 8:848, 1974.
86. Smith, B.T. and Torday, J.S., "Factors Affecting Lecithin Synthesis by Fetal
Lung Cells in Culture," Ped. Res. 8:848, 1974.
87. Smith, B.T., et al . , "Evidence for Different Gestation-Dependent Effects of
Cortisol on Cultured Fetal Lung Cells," J. Clin. Invst. 53:1518, 1974.
88. Smith, B.T., et al., "The Use of Monolayer Cell Cultures in the Study of
Fetal and Neonatal Pulmonary Cell Growth and Lecithin Synthesis," Chest
67 (No. 2) :22S, 1975. . .
REFERENCES (Continued)
89. Spellacy, W.M. , et al., "Human Amniotic Fluid Lecithin/Sphingomyelin Ratio
Changes with Estrogen or Glucocorticoid Treatment," Am. J. Ob. Gyn.
115:216, 1973.
90. Thannhauser, S.J., et al., "Isolation and Properties of Hydrolecithin
(Dipalmitoyl Lecithin) from Lungs: Its Occurrence in the Sphingomyelin
Fraction of the Lung Tissue," J. Biol. Chem. 166:669, 1946.
91. Tilsala, R. , et al., "Observations on the Perinatal Period of Infants of
Diabetic Mothers," Ann. Paed. Fenn. 13:9, 1967.
92. Tra-Dinh-De and Anderson, G. , "Hyaline-Like Membranes Associated with Diseases
of the Newborn Lungs: A Review of the Literature," Ob. Gyn. Survey 8:1,
1953.
93. Usher, R.H., et al., "Respiratory Distress Syndrome in Infants Delivered
by Cesarean Section," Am. J. Ob. Gyn. 88:806, 1964.
94. Usher, R.H., et al . , "Risk of Respiratory Distress Syndrome Related to
Gestational Age, Route of Delivery, and Maternal Diabetes," Am. J. Ob.
Gyn. 111:826, 1971.
95. Usher, R.H., et al., "Risk of Respiratory Distress Syndrome Related to
Gestational Age, Route of Delivexry/ and Maternal Diabetes," Am. J. Ob.
Gyn. 111:826, 1971.
96. von Neergaard, K. , "Neue Auffassungen uber eien Grundbegriff der Atemmechanik
Die Retraktionskraft der Lunge, Abhangig von der Oberf lachenspannung in den
Alveolen," Z. Ges . Exp. Med. 66:373, 1929.
97. Walsh, S.D. and Clark, F.R. , "Pregnancy in Patients on Long-Term Corticos-
teroid Therapy," Scot. Med. J. 12:302, 1967.
98. Wang, N.S., et al . , "Accelerated Appearance of Osmiophilic Bodies in Fetal
Lungs Following Steroid Injection," J. Appl . Physiol. 30:362, 1971.
99. Warmer, R. and Cornblath, M. , "Infants of Gestational Diabetic Mothers,"
Am. J. Dis. Child. 117:678, 1969.
100. Wigman, M.E., "Annual Summary of Vital Statistics, 1969," Pad. 47:461, 1971.
101. Wood, R.E. and Farrell, P.M., "Epidemiology of Respiratory Distress Syndrome
(RDS)," Ped. Res. 8:452, 1974.
102. Yackel , D.B. , et al . , "Adenocorticosteriod Therapy in Pregnancy," Am. J. Ob.
Gyn. 96:985, 1966.
103. Zachman, R.D., "The Enzymes of Lecithin Biosynthesis in Human Newborn Lungs.
III. Phorphorylcholine Glyceride Transferase," Ped. Res. 7:632, 1973.
Principals Interviewed
Dr. Mary Ellen Avery
Chief of Pediatrics
Boston Children's Hospital
Boston, Massachusetts
Dr. Louis Gluck
Department of Pediatrics
School of Medicine
University of California
San Diego, California
Dr. Leandro Cordero
Department of Pediatrics
The Ohio State University
College of Medicine
Columbus, Ohio
15-94
z
o
o
Z UJ
1-
„ £ c
a.
l5i
QC
s'S^
C)
UJ
I « -
I i J
Q
0 5 >
1 ± I
' O 2 I >
; 2 Q j^ <
>- s •:
so;
■^ f- u
>- I*' u.
^^1
ROLE OF SURFACTANT
DESCRIPTION AND ETIOLOGY ROLE OF STEROIDAL HORMONES
-VON NEEBGAARO, 1929
SURFACE TENSION IS CONTROLLING
IN THE ELASTIC RECOIL OF LUNGS
=ACTOR A
-PATTLE. 1955
SURFACTANT ACTlVIT
LUNG WASHES FROM P
SIMILAR HYSTERESIS EFFECTS COULD 8E
PRODUCED WITH LUNG SURFACTANT EXTRACTS
ESSURE^VOLUME
CURVES OF LUNGS, PHOSPHOL
. BASIS FOR PRESSURE, VOL
H/N
THERAPY
POSTNATAL
> HOCHHEIM. 19U3
INITIAL DESCRIPTION C
HYALINE MEMBRANE
• JOHNSON. 1923
FIRST ENGLISH DESCRIPTION OF PHM IN
ASSOCIATION WITH NEONATAL PNEUMONU
— FARBER. 1931
ETIOLOGY HYPOTHESIZED AND I
RESULT FROM ASPIRATION OF A
N
HN
H
COOES
HUMAN NEONATE
HUMAN
N
DETAILED DESCRIF
PATHOGENESIS AN
ABNORMALITIES Ih
N
nON OF INCIDEN
) DIAGNOSIS OF (
ASSOCIATION Wl
LHF LIVING HUMAN FETUS
(INCLUDING MOTHER)
NONLIVING NEONATE OR
SPONTANEOUS ABORTION
(AUTOPSY)
ANIMAL
RADtOGRAPhIC OESCHK
HETICULOGRANULAR Pt
GENERALIZED NEONATE
N
COMPOSITION OF 1
: MEMBRANES C
■MOOG. 1953
CORTISONE INDUCEI
THE FETAL INTESTIf
LUNG TISSUE ESTA
PHOSPHOLIPIDS IN
PHOSPHOLIPID CON
FROM MOTHER TO i
HN/H/ LHF
LHF/HN
'°';j°„; LHF
' BAOEN, 1972
HN
HN
ANTENATAL
LHF
RTUM GLUCOCORTK
J OCCURRING A
A
ETUSES
DEXAMETHASON
TO FETAL lamb:
- DELEMOS 1969
NJECTED WITH -
— DELEMOS, 1970
CORTISOL TREA
STIMULATING EF
SUGGEST THAT T
DIRECTLY
i MATURAT
.6S A
= CORTISOL <
RABBITS UNDERWENT RAPiO CYTODlFFERENTi- *
ATlON SHOWING DECREASED QUANTITIES OF A
i NUMBERS OF
ilC GLUCOCORTICOID
LONG BEFORE
ATEO FETUSES S
HN
N/A
LUCOCORTICOiC
FROM THE cono e
^ R05 INFANTS
HN
LHF
■* CONTINUES AS PREGNANCY PROGRESSES
Figure 4. Historiograph - Respiratory Distress Syndrome
ANIMAL MODELS
ANIMAL MODELS
Introduction and Summary
Because the objectives of this study included the identification of the
role of research involving living human fetuses in the four cases, and estimation
of the effect of a retrospective ban on such fetal research, the adequacy and
availability of animal models were considered. The foregoing descriptions of
each of the cases include information on animal models, but because of the impor-
tance of possible animal models to the conclusions drawn, this section of the
report has been prepared to centralize and expand on the information on animal
models for the research on living human fetuses. Summaries of the findings are
presented below.
Congenital Rubella Syndrome (Rubella Vaccine)
In the research that established the association of congenital rubella
syndrome with rubella in the mother, research on living human fetuses was not
involved, and therefore the question of possible animal models is irrelevant.
The association was established by studies on stillborns or neonates, which do
not fit the definition of research on living human fetuses as used in this report.
Establishment of the efficacy of the vaccine in preventing rubella and
therefore preventing congenital rubella syndrome again do not involve fetal
research — humans including nonpregnant women were used. In the determination
of the safety of vaccinating pregnant women, human fetuses were used. Studies
with animal models had shown that the live attenuated virus would not cross the
placental barrier. The inadequacy of these models became apparent after vacci-
nation of presumed nonpregnant women. Examination of the fetuses after induced
abortion showed the presence of the live attenuated virus. A study involving
pregnant women planning abortions was then done to verify the findings of the
few accidental vaccinations.
Amniocentesis
As a procedure, no record could be found of animal experimentation before
its suggested use in humans for therapy of hydramnios in 1882. Since that time
there has been considerable animal work, but differences in the amniotic fluid,
pelvic structure, trauma resistance, fluid barrier and placenta location exclude
animals as good models for the procedure. This conclusion was also reached by
the Yale group in the concurrent but separate study (Contract No. NOl-HU-5-2112).
As has been described earlier, amniocentesis played an important role in
characterizing and detecting Rh hemolytic disease and in the determination of
the degree of fetal lung maturation. It also allows the detection of sex and of
15-97
a number of genetic defects in the fetus. These methods depend on the study of
the fluid or of the cells either directly as harvested from the fluid or after
cell culture. Although animal models for most of these abnormalities are not
available, the harvesting and growth of cells can be demonstrated from animal
amniotic fluid. However, had not the amniocentesis procedure been available,
study of the human amniotic cells would not have been possible.
Isoimmunization (Rh Vaccine)
In this case, fetal research was vital in antenatal characterization and
detection of the disease. Detection of the disease in the fetus allowed the
determination of the need for antenatal transfusions, which drastically reduced
the number of in utero fetal deaths. No adequate animal models for Rh hemolytic
disease were available in the 1950s when these studies were begun. Intensive
study of immune diseases in primates was begun in the middle 1960s, and it now
appears that adequate models may exist, except for the problems of animal avail-
ability.
It must be pointed out that the fetal research necessary for the eradica-
tion of this disease depended on amniocentesis. In antenatal transfusion therapy,
the need for the transfusion is dictated by examination of the amniotic fluid.
Actual in utero fetal transfusions were preceded by animal studies.
Development of the Rh vaccine, once an understanding of the disease process
was gained, did not involve fetal research and the efficacy of the vaccine was
proved through use of male volunteers.
Respiratory Distress Syndrome
The role of surfactant in RDS was established by the study of neonate
victims of hyaline membrane disease. Methods to measure lung maturation (which
is predictive of RDS) were developed by both animal and human fetal research.
Because of interspecies differences in the rate of lung maturation, the latter
was necessary at the time it was done, since an adequate animal model did not
exist at that time. Fetal research was necessary for definitive conclusions to
be made.
In the development of antenatal glucocorticoid therapy, the effect of the
drug was established in animal studies. With animals, the glucocorticoid had
to be delivered directly to the fetus because the drug did not pass the placen-
tal barrier. Thus fetal research was necessary to establish that maternal admin-
istration of the drug in humans resulted in fetal uptake and consequent lung
maturation.
Congenital Rubella Syndrome
Since the isolation of the etiologic agent of rubella^ and its definitive
association with the congential rubella syndrome, 2 considerable effort has been
directed to establish an animal model for congenital infection by rubella virus.
In this regard, several animal species have been investigated. Congenital infec-
tion with natural "wild" rubella virus has been achieved in ferrets,-' rats,'' and
rabbits. 5. 6
Avila et al.,^ studied rubella virus induced congenital abnormalities in
the rat. Intramuscular inoculation of rubella virus into pregnant rats did not
have an effect on the developing embryo. Direct intrauterine injection of live
virus, however, caused an increase in resorption rate and retardation of post-
natal growth. These effects are also found in congenital rubella infection of
humans, ^'5 monkey s,^""'''^ and rabbits.^ In addition, ocular abnormalities in
3 of 64 offsprings of dams given direct intrauterine injections were observed.
However, repeated attempts to isolate virus from the offspring, from resorption
sites, and from retained placenta in mothers who failed to deliver were uniformly
unsuccessful.
The results from several laboratories indicate that the rabbit may be a
useful model for studying congenital rubella.^' ^' 1*'^^ Kono described eye defects,
including cataracts and microophthalmia in congenitally infected rabbits.^'
London et al.,-'^ have demonstrated that rubella virus caused congenital infection
when pregnant rabbits were inoculated on the sixth day of gestation. However,
there were no gross malformations in any fetuses, newborns, or babies.
In a study designed to determine the effect of vaccination on the trans-
placental transmission of rubella virus in rabbits, Cohen et al.,'^ demonstrated
that the effect of vaccination on congenital rubella in rabbits corresponds in
general to the observations in man 19-22 in that rubella infection occurred in
preimmunized animals. Further similarity in rubella infection in rabbit and man
was seen in the HAI response. The response in adult rabbits to vaccine was
varied and relatively poor in comparison with that following the injection of
low passage virus as noted in children with HPV-77 virus by Meyer et al.,23 and
in rabbits with HPV-77 (duck embryo) by Oxford and Potter. 24
The virus recovered from young rabbits of dams immunized with vaccine
virus and challenged with "wild" virus appeared to be "wild" virus. This is
consistent with the failure of Kono et al.,^ to isolate vaccine virus from off-
spring of immunized dams, indicating lack of passage of vaccine virus across the
placenta. As will be pointed out later, the human situation regarding transpla-
cental passage of vaccine virus is different from that of the rabbit. Further
differences in placental behavior were shown by the finding that IgM will not
cross the human placenta but will transverse the rabbit placenta.
In addition, a number of nonhuman primates have been evaluated for use as
model systems. These include baboons (Papio spp)^^'^^ chimpanzee (Pan troglo-
dytes),2= rhesus monkeys (Macaca mulatta) ,27-33 African green monkeys (Cerco-
pithecus aethiops) , ■''*"^^ cynomolgus monkeys (Macaca fascicularis) ,^* and patas
15-99
monkeys (Erythrocebus patas) . These animals are susceptible to rubella virus
infection; however, fetal abnormalities similar to congenital rubella in the
human^^ are rarely seen. ^'^ ^^' ■'^^ ^-^
Recently, Patterson et al.,'^' used marmosets to investigate susceptibility
to rubella virus infection. Marmosets were susceptible to infection by intra-
nasal inoculation. Infected animals began to excrete virus 12 days after inocu-
lation and continued to shed virus for 6-7 days. Significant hemagglutination-
inhibition antibody developed by 3-7 weeks postinoculation. The infection was
shown to spread naturally; one uninoculated animal of three exposed to the
infected group developed rubella HAI antibodies. However, there were signifi-
cant differences in rubella infection in marmosets compared to natural rubella
in humans. The infected animals did not develop clinical signs of infection.
Further, congenital rubella virus infection or anomalies were not present in the
fetuses of two female marmosets infected during early pregnancy. The value of
the marmoset model for congenital rubella, therefore, remains to be established.
Sever et al.,^^ reported on experimental rubella infection in pregnant
rhesus monkeys. Five pregnant monkeys were inoculated intravenously with rubella
virus during day 25 and 28 of gestation. None of the animals developed clinical
disease; however, virus was recovered from the nasopharynx of 4 of the 5 animals,
and the blood of 2 animals. Further, neutralizing antibody was detected on day
14 and complement-fixing antibody was present at six weeks. At the time of
delivery, 1 stillborn and 4 live offsprings were studied; there was no evidence
of infection or congenital malformation. However, 1 of 3 offsprings had anti-
body at six months of age, suggesting active antibody production due to undetec-
ted transplacental infection.
Parkman et al.,^^ reported that after rubella virus inoculation of 6 preg-
nant rhesus monkeys in the fourth week of gestation, virus was found in 3 of the
fetuses 10 to 31 days later.
Hopps et al.,'*° reported on a comparison of virulent low passage rubella
virus (LPV) and attenuated high passage rubella virus (HPV-77) infection in
12 pregnant rhesus monkeys. The animals were inoculated parentally during the
fourth week of gestation, 6 animals received HPV-77, and 5 were inoculated with
LPV. All of the animals developed antibodies. The animals were sacrificed 10
to 33 days after inoculation and specimens of maternal and fetal tissue were
collected for virus isolation. Rubella virus infection was transmitted to the
products of conception in 5 of the 6 animals inoculated with the virulent LPV
strain. However, in those 6 animals inoculated with the attenuated HPV-77 strain,
no rubella virus was isolated from maternal or fetal specimens taken 17, 21, and
28 days after inoculation.
From what has been reported for the animal model systems evaluated, it is
clear that the experimental animals behave differently when exposed to rubella
virus. With most animals, congenital infection with natural "wild" rubella virus
can occur, but in many cases, congenital malformations are absent. I'Jhere con-
genital defects have been reported, they primarily involve the eye. The spectrum
of congenital abnormalities in animal model systems does not approach that found
in humans.
15-100
A most important consideration when discussing the appropriateness of
animal models is that vaccine virus did not cross the placenta and infect the
fetus. Based on this, the vaccine could be considered safe for use in pregnant
women. This, however, was not the case in humans where it was shown that vac-
cine virus did cross the placenta and did infect the fetus.
To quote from testimony given by Dr. Michael Oxman, Harvard Medical
School, before the Massachusetts State Legislature, "When rubella vaccine was
first developed, an important question was its safety for the fetus — in other
words, would the vaccine virus behave like the natural 'wild' rubella virus and,
after infecting the mother, cross the placenta to infect and damage the fetus?
Tests were done in pregnant monkeys and whereas the 'wild' rubella virus did
cross the placenta and did infect the monkey fetus, just as it does in the human,
the vaccine virus did not. This suggested that administration of riibella vaccine
to pregnant women might not be hazardous to the fetus. Fortunately, however,
physicians in several medical centers then performed the same study in women
scheduled for therapeutic abortions. After a full explanation of what was
involved, a number of women volunteered and received rubella vaccine 11 to 30
days prior to their abortion. Subsequent examination of the aborted fetal tis-
sues showed that, in contrast to the results in the monkey, the vaccine did cross
the human placenta and did infect the human fetus. On the basis of this informa-
tion, the administration of rubella vaccine to pregnant women or to women who
might become pregnant within 60 days of vaccination is prohibited."
Based on these considerations, it is clear that animal models have been
inappropriate for congenital rubella and in some cases, misleading in terms of
vaccine safety.
15-101
REFERENCES
1. Parkman, P.D., Buescher, R.L., et al., "Recovery of Rubella Virus from Army
Recruits," Proc. Soc . Exp. Biol. Med. 111:225, 1962.
2. Selzer, G., "Virus Isolation, Inclusion Bodies, and Chromosomes in a Rubella-
Infected Human Embryo," Lancet 2:336, 1963.
3. Rorke, L.B., Fabiyi, A., et al. , "Experimental Cerebrovascular Lesions in
Congenital and Neonatal R\ibella Virus Infections of Ferrets," Lancet
2:153, 1968.
4. Cotlier, E. , Fox, J., et al., "Pathogenic Effects of Rubella Virus on Embryos
and Newborn Rats," Nature (Lond.) 217:38, 1968.
5. Kono, R. , Hayakawa, Y., et al . , "Experimental Vertical Transmission of Rubella
Virus in Rabbits," Lancet 1:343, 1969.
6. London, W.T., Fuccillo, D.A. , et al., "Concentration of Rubella Virus Antigen
in Chondrocytes of Congenitally Infected Rabbits," Nature (Lond.) 226:172,
1970.
7. Avila, L. , Rawls, W.E., et al., "Experimental Infection With Rubella Virus.
I. Acquired and Congenital Infection in Rats," J. Inf. Dis. 126:585, 1972.
8. Ingalls, T.H. , Plotkin, S.A., et al., "Rubella: Epidemiology, Virology, and
Immunology," Am. J. Med. Sci. 253:349, 1967.
9. Cooper, L.Z. and Krugman, S., "Clinical Manifestations of Postnatal and
Congenital Rubella," Arch. Ophthalmol. 77:434, 1967.
10. Delahunt, C.S. and Rieser, N. , "Rubella-Induced Embryopathies in Monkeys,"
Am. J. Obstet. Gynecol. 99:580, 1967.
11. Parkman, P.D., Phillips, P.E., et al., "Experimental Rubella Virus Infection
in Pregnant Monkeys," Am. J. Dis. Child. 110:390, 1965.
12. Sever, J.L., Meier, G.W. , et al., "Experimental Rubella in Pregnant Rhesus
Monkeys," J. Infect. Dis. 116:21, 1966.
13. Amstey, M.S., "Intraamniotic Inoculation of Rubella Virus," Am. J. Obstet.
Gynecol. 104:573, 1969.
14. Belcourt, R.J. P., Wong, F.C. , et al . , "Growth of Rubella Virus in Rabbit
Foetal Tissues and Cell Cultures," Canad. J. Pub. Hlth. 56:253, 1966.
15. Cohen, S.M. , Collins, D.N., et al., "Transplacental Transmission of Rubella
Virus Infection in Rabbits," Appl . Microbiol. 21:76, 1971.
15-102
REFERENCES (Continued)
16. London, W.T. , Fuccillo, D.A., et al . , "Congenital Rubella in Rabbits,"
Int. Symp. Rubella Vaccines, London, 1968. Symp. Ser . Immunobiol. Stand.
11:121, 1969.
17. Kono, R.M. , Hiviyhy, Y. , et al., "Experimental Vertical Transmission of
Rxibella Virus in Rabbits," Proc. First Intl. Cong, in Virology, Helsinki,
Finland, 1968.
18. Cohen, S.M., Deibel, R. , et al., "Effect of Rubella Vaccine on Transplacental
Rubella Virus Infection in Rabbits," J. Lab. Clin. Med. 80:179, 1972.
19. Meyer, H.M. , Jr., Parkman, P.D., et al., "Clinical Studies with Experimental
Live Rubella Virus Vaccine (Strain HPV-77) : Evaluation of Vaccine-Induced
Immunity," Am. J. Dis . Child. 115:648, 1968.
20. Schiff, G.M. , Donath, R. , et al., "Experimental Rubella Studies. 1. Clinical
and Laboratory Features of Infection Caused by the Brown Strain Rubella
Virus. 2. Artificial Challenge Studies of Adult Rxobella Vaccines," Am. J.
Dis. Child. 118:269, 1969.
21. Wilkens, J., Deedom, J.M., et al., "Reinfection With Rubella Virus Despite
Live Vaccine Induced Immunity: Trials of HPV-77 and HPV-80 Live Rubella
Virus Vaccines and Subsequent Artificial and Natural Challenge Studies,"
Am. J. Dis. Child. 118:275, 1969.
22. Horstmann, D.M. , Liebhaber, H. , et al., "Rubella: Reinfection of Vaccinated
and Naturally Immune Persons Exposed in an Epidemic," N. Eng. J. Med.
283:771, 1970. . , , . ,
23. Meyer, H.M., Jr., Parkman, P.D., et al., "Attenuated Rubella Viruses,
Laboratory and Clinical Characteristics," Am. J. Dis. Child. 118:155, 1969.
24. Oxford, J.S. and Potter, C.W. , "An Immunologic Marker Technique for the
Cendehill Vaccine Strain of Rubella Virus," J. Immunol. 105:818, 1970.
25. Horstmann, D.M. , "The Use of Primates in Experimental Viral Infections -
Rubella and the Rv±iella Syndrome," Ann. N.Y. Acad. Sci. 162:594, 1969.
26. Kalter, S.S. and Heberling, R.L., "Comparative Virology of Primates,"
Bacterial. Rev. 35:310, 1971.
27. Amstey, M.S., "Intraamniotic Inoculation of Rubella Virus," Am. J. Obstet.
Gynecol. 104:573, 1969.
28. Delahunt, C.S., "Rubella-Induced Cataracts in Monkeys," Lancet 1:825, 1965.
29. Delahunt, C.S. and Rieser, N. , "Rubella-Induced Embryopathies in Monkeys,"
An?. J. Obstet. Gynecol. 99:580, 1967.
REFERENCES (Continued)
30. Meyer, H.M., Parkman, P.D., et al., "Attenuated Rubella Virus. II. Production
of an Experimental Live-Virus Vaccine and Clinical Trial," New Eng . J. Med.
275:575, 1966.
31. Parkman, P.D., Phillips, P.E., et al., "Experimental Rubella Virus Infection
in the Rhesus Monkey," J. Immunol. 95:743, 1965.
32. Parkman, P.D., Phillips, P.E., et al., "Experimental Rubella Virus Infection
in Pregnant Monkeys," Am. J. Dis . Child. 110:391, 1965.
33. Sever, J.L., Meier, G.W. , et al., "Experimental Rubella in Pregnant Rhesus
Monkeys," J. Infect. Dis. 116:21, 1966.
34. Cabasso, V.J., Stebbins, M.R. , et al., "Attenuation of Riobella Virus: Studies
in Monkeys and Man," J. Lab. Clin, Med. 70:429, 1967.
35. Sigurdardottir, B.K., Swan, K.F. , et al . , "Association of Viruses with Cases
of Rubella Studied in Toronto: Propagation of the Agent and Transmission
to Monkeys," Canad, Med. Assoc. J. 88:128, 1963.
36. Okuno, Y. , Minekawa, Y., et al., "Studies on Live Rubella Vaccine. I. Propa-
gation of Rubella Virus in Developing Chick Embryos and Its Laboratory
Characterization," Biken J. 11:235, 1968.
37. Draper, C.C. and Lawrence, G.D., "Susceptibility of Erythrocebus Patas
Monkeys to Rubella Virus," J. Med. Microbiol. 2:249, 1969.
38. Cooper, L.Z. and Krugman, S. , "Clinical Manifestations of Postnatal and
Congenital Rubella," Arch. Ophthalmol. 77:434, 1967.
39. Patterson, R.L., Keren, A., et al., "Experimental Ri±iella Virus Infection
of Marmosets (Saguinus Species)," Lab. Animal Sci . 23:68, 1973.
40. Hopps, H.E., Parkman, P.D., et al., "Laboratory Testing in Ri±)ella Vaccine
Control," Am J. Dis. Child. 118:338, 1969.
15-104
Amniocentesis
When considering an alternate animal model in lieu of amniocentesis on
humans and fetal research, one should differentiate between the amniocentesis
procedure per se, and the diagnostic and therapeutic procedures performed via
amniocentesis. In both situations the possibilities of an alternate animal
model must be considered for the procedure per se or as a model for developing
a diagnostic or therapeutic procedure. Thus, this section will attempt to out-
line the possible alternate animal models for each situation.
alternate Animal Models for Developing Amniocentesis Procedure
Various animal models have been considered for evaluating amniocentesis,
but unlike the human, the embryos of domestic animals (sheep, cattle, horses,
pigs, and cats) have large allantoic vesicles and, as a result, contain large
volumes of both allantoic and amniotic fluids.-' Marsh et al.,^ indicate in their
paper that the amniotic volume patterns do differ from animal to animal. In the
cat and guinea pig, amniotic fluid shows a slight fall in volume followed by a
climb to term. The rat, hamster, mouse, and rabbit show a very rapid decrease
to virtual disappearance near term while moderate to rapid decreases near birth
are characteristic of the sow and cow. Sheep and human beings show a stationary
volume or slight decline near birth once a maximum is attained. A hair satura-
tion factor may affect the amniotic volume in some animals because the amniotic
fluid attaches more and more to fetal hair as term approaches.^ Thus, it is
apparent that many of the potential animal models are unsatisfactory because they
show a distinct difference from humans in the volume of amniotic fluid present
during the gestational period. In addition, the only animal models which might
be suitable for developing the technique of transabdominal amniocentesis should
be monovular and possess a unicornuate uterus.^ This statement is based upon
the fact that the technique could not be satisfactorily evaluated either in uteri
containing multiple fetuses or in a bicornuate uterus because of structural dif-
ferences relative to humans. These restrictions reduce the potential animal
model to higher primates, e.g., monkeys, chimpanzees or baboons.
In considering a higher primate, one must examine the similarities and
differences between it and humans. Some of the similarities, although not nec-
essarily related to the procedure per se, would include the following:
(1) Access to the rhesus monkey fetus in utero is possible and sam-
ples of fetal body fluids can be obtained throughout gestation."
(2) The embryological studies of Heuser and Streeter^ and Streeter ^
have demonstrated that the anatomical and temporal aspects of
morphological development in the macaque is similar to the human
embryo in most respects throughout the critical period of dif-
ferentiation.
15-105
(3) It has been shown that there is a similarity in the rhesus
monkey and humans as regards embryotoxity , i.e., identical
teratological manifestations as seen in humans have been
produced in rhesus monkeys regarding radiation, androgenic
hormones and thalidomide syndrome.'
(4) Placental structure in rhesus monkeys is highly analogous
to the httman during the later stages of pregnancy.''^
(5) The virtual identity between female human and monkey repro-
ductive physiology has been established by many investiga-
tors.'
As a result of human amniocentesis, some investigators are now routinely
performing amniocentesis in subhuman primates.® This would lead one to believe
that indeed the higher primates could have been used as models to perfect the
technique. However, the reasons cited below are also considered valid by some
investigators for not employing primates in developing amniocentesis as a pro-
cedure. These include the following:
(1) Significant difference in the amniotic fluid: fetal size
ratio relative to humans leading to invalid extrapolation
of a technique developed in these animals to humans, espe-
cially for late second and third trimester amniocentesis.
(2) Difference in skin and subcutaneous tissue composition such
that development of skill by the operator would not be appli-
cable to humans.
(3) Difference in boney pelvis structure to the extent that this
hard tissue, in many cases, would not allow invasion of the
uterus at the desired human site.^
(4) Placental position in some of these species is characteris-
tically anterior so that transabdominal entry into the uterus
would always be through the placenta. ^
(5) Size of the uterus is always smaller at equivalent stages of
pregnancy.
(5) Size differences also introduce the problem of needle diameter
and length. Properly sized needles for humans could not be
determined without direct evaluation on humans.
(7) The simian uterus is resistant to trauma^° which suggests that
premature delivery might occur if the techniques developed in
primates were extended to humans.
(8) There is a fluid barrier around the amnion in some monkeys
which provides a self-sealing mechanism to prevent losses of
amniotic fluid from the puncture site.® Loss of amniotic fluid
following amniocentesis has been implicated in various
anomalies. One case of Potter's facies has been reported
in a human newborn after prolonged leakage of amniotic
fluid."
(9) During the later stages of gestation the volume of amni-
otic fluid available would be decreasing due to the hair
saturation factor as mentioned earlier.
In the evaluation of amniocentesis in mice and rats, numerous anomalies
including malformation of the extremities, microstomia, short umbilical cord and
particularly cleft palate were reported after the procedure was performed. ^^"^^
These animal experiments in mice and rats showed that cleft palate could be pro-
duced with 100 percent frequency if amniocentesis was carried out in a certain
stage of pregnancy prior to palate closure. The similarities between the defects
produced by amniocentesis in rats and mice and human cases of cleft palate led
Poswillo^ to suggest that amniocentesis might produce the same effect on human
fetuses during the first trimester of development. It must be remembered at
this time that only a very limited number of amniocenteses have been performed
during the late first trimester period.
Poswillo^ has shown that a suitable animal model, the Macaca irus monkey,
does exist for demonstrating closure of the posterior palate at day 46 of devel-
opment, and, according to Kraus et al. ,^^ the human palate closes at day 47.
There results showed that the congenital defects produced in the lower species
(rats and mice) by amniotic-sac puncture were not reproduced in the M. irus mon-
key. Thus, it would appear on the basis of these limited data that the hazard
of inducing congenital malformations, e.g., cleft palate, is far less than that
predicted by the rat and mouse studies. Furthermore, thousands of amniocenteses
have been performed in hximans during the second and third trimester of pregnancy
and the complications noted are less than one percent. This would be additional
proof that amniocentesis per se does not cause congenital malformations as
observed in the rat and mice studies.
Although Poswillo* has demonstrated an animal model which closely parallels
the human embryo during the first trimester of development, it is very doubtful
if this animal model can be adequately extrapolated to cleft palate formation in
human embryos. The reasons for this conclusion are as follows:
(1) The most significant reason is the fluid barrier surrounding
the amnion in M. irus which provides a self-sealing mecha-
nism to occlude puncture wounds of both the amnion and cho-
rion. This self-sealing mechanism has not been demonstrated
in humans, and, if Trassler et al.,22 are correct in their ' »
assessment of the malformations caused in rats and mice,
i.e., a loss of amniotic fluid resulting in oligohydramnios
induces the abnormalities seen in rat and mice fetuses, such
a loss of amniotic fluid during the first trimester of devel-
opment could prove disasterous to human embryos.
15-107
(2) It has not been demonstrated that a correlation exists
between the volumes of fluid in the chorionic cavities
of both species, because this would be the only prac-
tical method of obtaining fluid prior to 50 days of
development. 3
(3) Most investigators agree that the earliest acceptable
time that amniocentesis should be performed in humans is
14 weeks, almost twice the length of time that cleft pal-
ate could be detected.
In conclusion, a ban on human fetal research with regard to developing
improved techniques of amniocentesis would have resulted in its nonutilization
due to inadequate or inappropriate alternate animal models with which to develop
and perfect the method. The ramifications of the unavailability of this tech-
nique are overwhelming considering the multitude of highly useful and desirable
diagnostic and therapeutic procedures which rely on amniocentesis.
Alternate Animal Models for the Diagnostic and Therapeutic Techniques Developed
as a Result of Amniocentesis
If it is accepted, as in the preceeding section, that the development of
amniocentesis was dependent upon research involving living hxanan fetuses, the
effects of a ban on human fetal research in the antenatal diagnosis and therapy
via amniocentesis would have been far reaching indeed.
The diagnostic and therapeutic methods developed via amniocentesis include
the following:
(1) Analysis of components in amniotic fluid
(2) Detection of genetic defects
(3) Detection of Rh isoimmunization
(4) Detection of fetal maturity
(5) Providing relief from polyhydramnios
(6) Induction of a therapeutic or elective abortion.
An important question in determining the effect of a ban on human fetal
research is whether or not an animal model could have been substituted for the
advances made to date regarding prenatal diagnosis and therapeutic procedures
developed as a result of amniocentesis. Each of the above indications for per-
forming amniocentesis will be considered. The development of alternate animal
models for Rh isoimmunization and the respiratory distress syndrome will be dis-
cussed in those sections.
15-108
Analysis of Amniotic Fluid ■
In comparing the materials found in amniotic fluid of humans and other
species, it is apparent that some materials are found in both while in other
instances there is a distinct difference. For instance, the amniotic fluid of
foetal lambs contains lecithin, sphingomyelin, and phosphatidyl ethanolamine^*
as does human amniotic fluid. ^^ In addition, observations show that both human
fetal and monkey fetal liquors contain many of the major protein components of
serum.^^ However, the fact one particular protein was shown to be present in
three species of monkeys but was absent from hiiman liquor suggested a difference
in fetal metabolism.^®
Further indications of a possible difference in the metabolism of compounds,
i.e., lactic acid, has been demonstrated.^'' The transfer of lactic acid from
the human fetus to the mother indicated a turnover rate of 1.4 minutes while
the turnover rate from the monkey fetus to the mother was in excess of fifteen
minutes. As a result, Friedman et al. ,^' concluded that lactic acid is not a
major end-product of fetal metabolism in primates.
Other animals have afforded valuable information concerning the source of
amniotic fluid and the maternal-fetal relationship to various components found
in amniotic fluid. Both the fetal lamb^® and the monkey fetus ^^ have been dem-
onstrated upon sodium depletion to respond to the deficiency like a sodium defi-
cient adult by restricting sodium losses in the urine and by excreting water.
The rhesus monkeys as well as the guinea pig, rabbit, calf and rat demonstrate
selective absorption of antibodies and of radioactive labeled plasma proteins ^°"^*
but the mechanism of absorption differs. Heterologous albumin has been shown
immunologically to reach the fetus in the rabbit, ^^ but Whipple et al.,^' found
that some labeled serum proteins were taken up in rabbits but not in the dog
while labeled serum albumin, 3-globulin and Y~globulin were transferred to the
guinea pig fetus. ^^
The anatomical membrane concerned with selective transmission in orders
other than primates has been considered to be the endoderm of the gut or the
yolk sac. On the basis of the evidence of the above comparative studies it was
postulated that transmission in man and other primates was also by way of the
amniotic fluid and the fetal gut."" However, the anatomy of the placental sys-
tems and fetal membranes vary widely among different orders of animals. The
human being possesses a specialized haemochorial placental system quite unlike
that of other orders, and the yolk sac in mid and late pregnancy is entirely
vestigial. *° A comparable placental system is again found only among the
catarrhine monkeys and anthropoid primates (apes) with the placenta of the rhesus
monkey resembling the human placenta very closely in later stages of pregnancy.^
The experiments of Bangham ^°' ''^ with radioactive labeled proteins injected
into pregnant rhesus monkeys provide evidence that there is a selective transfer
of certain maternal serum proteins across the placenta and that the amniotic
fluid plays an unimportant part, if any, in the transmission of proteins to the
primate and human fetus. There is also evidence using labeled lactic acid injec-
ted into the fetal circulation of the rhesus monkey that the maternal and fetal
organisms freely exchange metabolites^'' in both directions across the placenta.
Thus, these few correlations with regard to amniotic fluid concentrations of
certain metabolites and proteins should caution against too great a tendency to
interpolate results in one or several species or orders to the human situation.
Detection of Genetic Defects
Knowledge of the mitotic and meiotic behavior of chromosomes is one area
where animal models have contributed to the present state of advanced techniques
which permit visualization of the chromosomes both in human lymphocytes and in
cells cultured from amniotic fluid obtained by amniocentesis in human pregnan-
cies. The mechanisms leading to abnormal behavior of the chromosomes as seen
in nondisjunction and in balanced and unbalanced chromosome translocations have
long been known both in lower forms and in mammals .*2-45 Nondisjunction (fail-
ure of members of a chromosome pair to separate equally at meiosis in ovum and
sperm) is the primary cause of the trisomies which are the major type of chro-
mosome aberration producing gross malformation in human concepti and newborns.
Down's syndrome (mongolism) is the most common trisomy in human births and con-
sists of three members of chromosome pair number 21, instead of the normal pair.
A more rare but inheritable abnormality of the human chromosomes which can lead
to an unbalanced condition of chromosome number and to congenital malformation
is known as a translocation. The most common translocation in humans is D/G
(one chromosome of the D type is permanently attached to one of the G type) .
Unlike the true trisomy which is an "accident" of cell division in meiosis and
therefore is not inheritable, the translocation can be carried in a balanced
state in a normal human "carrier" and can be inherited from the "carrier" in an
unbalanced form which produces congenital malformations.
Models of the aneuploidies , of which trisomies like Down's syndrome are
but a type, have also been known for the domestic cat, mouse, and hamster.
Although these chromosome aberrations have models, the models cannot give us any
clinical indications of what specific additions, losses or translocations a given
human chromosome will present. This is because the gene content of the human
chromosome differs from that of its model.
Recent advances in inducing banding of specific chromosomes and in forma-
tion of mouse/man somatic cell hybrids have brought about rapid advances in
assigning specific human genes to specific chromosomes and in establishing groups
of genes which are linked (closely located) on the same chromosome. This infor-
mation has long been available in corn, tomato, wheat, and the fruit fly, mouse
and hamster. The knowledge of gene location on specific chromosomes and of
groups of genes which are closely linked will enhance the value of amniocentesis
in human pregnancies. With this additional knowledge it is possible to combine
biochemical studies of the amniotic fluid contents or cultured amniotic fluid
cells with specific chromosome patterns or known genes to which the congenital
malformation may be linked.
The above technique has been postulated as an aid in detecting fetuses
affected with sex-linked diseases where accurate sex-determination may be made
from studies of presence or absence of both the X and Y (F body) chromosomes,
while biochemical determinations of a linked gene such as the ABH secretor or
15-110
G5PD status are made in families or subpopulations where these genes are common.
These techniques can be refined in an animal model such as a mouse in which amni-
otic sex chromatin and fetal sexing are demonstrable''^ and, in v;hich much infor-
mation concerning gene location and linkages are already available, but will have
to be adapted to fit the specific gene defect of the human subject.
In summary, there are no known animal models for identifying the X-linked
diseases presently detectable by amniocentesis in the human which include the
Lesch-Nyhan and Hunter's syndromes, and Fabry's disease. The same situation
would prevail for the cytogenetic studies used to detect chromosomal aberrations
since the chromosomal number and gene content is different. Thus, a suitable
animal model does not exist for detecting chromosomal aberrations. In addition,
there is no animal model for the various inborn errors of metabolism which have
been identified by antenatal diagnosis.
Diagnosis of the major congenital malformations of the central nervous
system such as anencephaly and spina bifida (open spine) have been the most dif-
ficult to predict from family data and from amniotic fluid since there has been
no specific biochemical or cytological change associated with this category of
human malformation. Attempts have been made to determine the presence of anen-
cephaly with or without spina bifida by increase in optical density of the amni-
otic fluid at 450nm (A OD450) provided the pregnancy is not complicated by Rh
sensitization. "^"-^ in general it may be concluded from the previously cited
work that in the last trimester of pregnancy, an antenatal diagnosis of upper
intestinal obstruction may be made if there is an increase in A OD450, and not
associated with Rh sensitization.
Another approach to diagnosis of central nervous system malformations from
amniotic fluid is the reduction in 5-hydroxy-indoleacetic acid (5HIAA) levels
as reported by Emery et al.^^ Reduction of 5HIAA was observed, but no change
was observed in a number of other substances present in amniotic fluid nor was
reduction of 5HI7^ levels observed in cases of polyhydramnios where the fetus
was normal.
A new approach to the diagnosis of central nervous system malformations
has been postulated by the detection of a specific biochemical substance in
amniotic fluid and demonstrated in fetuses of the Lewis rat who were affected
with spina bifida. ^^ The presence of specific proteins (3-trace and y-trace)
in human cerebrospinal fluid (CSF) has been well established and their study ^^
was undertaken to investigate whether closure malformations of the central ner-
vous system (spina bifida) would cause a rise in amniotic fluid alpha-foetoprotein
levels. It has been suggested that leakage or transudation of fetal blood com-
ponents or CSF directly into the amniotic fluid would cause a rise in the alpha-
foetoprotein concentration. The authors demonstrated that a 3-trace-like protein
of rat CSF could be demonstrated in the amniotic fluid of embryos exhibiting
spina bifida.
These results clearly point to the development of an antenatal diagnosis
for spina bifida, but the authors are aware that a true communication between
the central nervous system and the amniotic fluid is a prerequisite for the
detection of 3-trace-like protein. While the preceding article postulates an
15-111
animal model in the much needed area of human malformation with hitherto unknown
biochemical relation to composition of amniotic fluid, its usefulness in predic-
ting closure malformation in human pregnancy has yet to be demonstrated.
Detection of Fetal Maturity
A common problem in clinical obstetrics is the precise determination of
gestational age and fetal maturity. Peterson et al.,54 have shown that the
rhesus monkey can be used as a model for the ultrasonic measurement of the bipa-
rietal diameter of the fetal head. After approximately 120 days gestation in
the rhesus monkey (Macaca mulatta) , a noticeable decline in the rate of growth
of the fetal skull was observed via these biparietal measurements, data which
are in agreement with trends noted in similar studies of the human fetus.
In addition to the above observation, amniotic fluid creatinine levels in
the last third of pregnancy in Macaca mulatta are comparable to values in hi-imans,
but no clear relationship exists between the creatinine concentration and the
duration of pregnancy. Similarly, the bilirubin concentration in the amniotic
fluid does not show a change with reference to gestational age nor does osmolal-
ity appear to be a predictor of fetal age and growth in the rhesus monkey.^"
All these latter determinations have proven of value for estimating human gesta-
tional age and fetal maturity. Thus, there is a clear separation between the
two species and the monkey is not considered a totally satisfactory model for
detecting fetal maturity.
Polyhydramnios . The polyhydramnios condition has been observed in diabetic
monkeys,^'' and, as a result, amniocentesis could therefore be performed on such
a species to demonstrate the effect of fluid removal. However, a primary disad-
vantage in using monkeys as a polyhydramnios model would be the difficulty in
breeding primates which are in captivity, developing a colony of diabetic mon-
keys and, the effect of diabetes on the fetal development of the monkey.
Induction of Abortion. Any of the higher primates presumably could be used
for developing the abortif acients to be used for inducing an abortion in conjunc-
tion with amniocentesis. However, regarding the amniocentesis procedure itself,
the higher primates are considered an unsatisfactory model for reasons cited
earlier.
REFERENCES
1. Arthur, G.H., "The Fetal Fluids of Domestic Animals," J. Reprod. Pert. Suppl.
9:45, 1969.
2. Marsh, R.H., King, J.E., and Becker, R.F., "Volume and Viscosity of Amniotic
Fluid in Rat and Guinea Pig Fetuses Near Term," Am. J. Obst. & Gyn.
83 (No. 4) :487, 1963.
3. Dorfman, A., Antenatal Diagnosis, Chicago: The University of Chicago Press,
1972, p. 286. , , . ,
4. Plentl, A.L. and Friedman, E.A., "Isotope Tracer Studies on the Carbon
Dioxide Exchange in Pregnant Primates," Am. J. Obst. S Gynec. 84 (No. 9):
1242, 1962.
5. Heuser, C.H. and Streeter, G.L., Carnegie Inst. Cont. Embryol. 29:15, 1941.
6. Streeter, G.L., "Developmental Horizons in Human Embryos," Carnegie Inst.
Cont. Embryol. 34:165, 1951. . .
7. Wilson, J.G., "Use of Rhesus Monkeys in Teratological Studies," Fed. Proc .
30 (No. 1) :104, 1971.
8. Amoroso, B.C., "Placentation, " Marshall' s Physiology of Reproduction, Vol. 2,
London: Longmans, Green and Co., 1952, p. 127.
9. Poswillo, D., "Experimental First-Trimester Amniocentesis in Nonhuman
Primates," Teratology 6:227, 1972.
10. Nathan, D. , Drug Research Reports 18 (No. 8):3, 1975.
11. Bain, A.D., Smith, I.I., and Gauld, I.K. , "Newborn After Prolonged Leakage
of Liquor Amnii," Br. Med. J. 2:598, 1964.
12. Poswillo, D. , "Observations of Fetal Posture and Casual Mechanism of Con-
genital Deformity of Palate, Mandible and Limbs," J. Dent. Res. 45:584,
1966. ; , _ -
13. Walter, B.E., "Effect on Palate Development of Mechanical Interference with
Fetal Environment," Science 130:981, 1959.
14. DeMyer, W. and Baird, I., "Mortality and Skeletal Malformations from Amnio-
centesis and Oligohydramnios in Rats: Cleft Palate, Clubfoot, Microstomia
and Adactyly," Teratology 2:33, 1969.
15. Singh, S. and Singh, G. , "Hemorrhages in the Limbs of Fetal Rats After
Amniocentesis and Their Role in Limb Malformations," Teratology 8:11, 1973.
15-113
REFERENCES (Continued)
16. Poswillo, D. , "The Etiology and Surgery of Cleft Palate with Micrognethia, "
Ann. Roy. Coll. Surg. 43:61, 1968.
17. Poswillo, D. and Roy, L. J. , "The Pathogenesis of Cleft Palate: An Animal
Study," Br. J. Surg. 52:902, 1965.
18. Poswillo, D. and Sopher, D. , "Malformation and Deformation of Animal Embryo,"
Teratology 4:498 (abst) , 1971.
19. Kendrick, E.J. and Field, L.E. , "Congenital Anomalies Induced in Normal and
Adrenalectomized Rats by Amniocentesis," Anat. Rec. 159:353, 1967.
20. Kino, Y. , "Reductive Malformations of Limbs in the Rat Fetus Following
Amniocentesis," Cong. Anom. 12:35, 1972.
21. Walker, B.E., "Correlation of Embryonic Movement with Palate Closure in
Mice," Teratology 2:191, 1969.
22. Trasler, D.G., Walker, B.E. , and Fraser, F.C., "Congenital Malformations
Produced by Amniotic-Sac Puncture," Science 124:439, 1956.
23. Kraus , B.S.H., Kitamura, H. , and Latham, R.A. , Atlas of Developmental Anatomy
of the Face, New York: Hocher, 1966, p. 77.
24. Fujiwara, T. , Adams, F.H., and Scudder, A., "Fetal Lamb Amniotic Fluid:
Relationship of Lipid Composition to Surface Tension," J. Pediat. 65:824,
1964.
25. Helmy, F.M. and Hack, M.H. , "Comparison of the Lipids in Maternal and Cord
Blood and of Human Amniotic Fluid," Proc. Soc . Exper. Biol. & Med. 110:91,
1962.
26. Bangham, D.R. , Hobbs , K.R., and Tee, D.E.H., "The Origin and Nature of
Proteins of the Liquor Amnii in the Rhesus Monkey; A New Protein with
Some Unusual Properties," J. Physiol. (London), 158:207, 1961.
27. Friedman, E.A.; Gray, M.J.; Grynfogel, M. ; Hutchinson, D.L.; Kelly, W.T.;
and Plentl, A.A. , "The Distribution and Metabolism of C-*- -Labeled Lactic
Acid and Bicarbonate in Pregnant Primates," J. Clin. Invest. 39:227, 1960.
28. Phillips, G.D. and Sundaram, S.K., "Sodium Depletion of Pregnant Ewes and
Its Effects of Foetuses and Foetal Fluids," J. Physiol. 184:889, 1966.
29. Friedman, E.A.; Gray, M.J.; Hutchinson, D.L.; and Plentl, A.A., "The Role
of the Monkey Fetus in the Exchange of the Water and Sodium of the
Amniotic Fluid," J. Clin. Invest. 38:961, 1959.
30. Bangham, D.R. , Hobbs, K.R. , and Terry, R.J., "Selective Placental Transfer
of Serum Proteins in the Rhesus," Lancet 274:351, 1958.
15-114
REFERENCES (Continued)
31. Bangham, D.R. , Hobbs , K.R. , and Tee, D.E.H., "The Transmission of Serum
Proteins from Foetus to Mother in the Rhesus Monkey; Indwelling Cannulation
of the Foetus Without Interruption of Pregnancy," Lancet 279:1173, 1960.
32. Dancis, J. and Shafran, M. , "The Origin of Plasma Proteins in the Guinea-
Pig Foetus," J. Clin. Invest. 37:1093, 1958.
33. Schechtman, A.M. and Abraham, K.C. , "Passage of Serum Albiomins from Mother
to Foetus," Nature (London), 181:120, 1958.
34. Batty, I.; Brambell, F.W.R.; Hemmings , W.A.; and Oakley, C.L., "Selection
of Antitoxins by the Foetal Membranes of Rabbits," Proc. Roy. Soc. B.
142:452, 1954.
35. Myant, N.B. and Osorio, C, "Thyroxine-Binding Protein in the Serum of
Rabbit Foetuses," Nature (London), 182:866, 1958.
36. Deutsch, H.F., "Fetuin: The Mucoprotein of Foetal Calf Serum," J. Biol.
Chem. 208:669, 1954.
37. Halliday, R. , "The Absorption of Antibody from Immune Sera and from Mixtures
of Sera by the Gut of the Young Rat," Proc. Roy. Soc. B. 148:92, 1957.
38. Clark, S.L., "The Ingestion of Proteins and Colloidal Materials by Columnar
Absorptive Cells of the Small Intestine in Suckling Rats and Mice,"
J. Biophys. Biochem. Cytol . 5:41, 1959.
39. Whipple, G.H.; Hill, R.B. ; Terry, R. ; Lucas, F.V. ; and Yuile, C.L., "The
Placenta and Protein Metabolism. Transfer Studies Using Carbon -Labelled
Proteins in Dogs," Excerpt. Med. 101:617, 1955.
40. Brambell, F.W.R.; Brierly, J.; Halliday, R. ; and Hemmings, W.A. , "Transference
of Passive Immunity from Mother to Yo\ang," Lancet 266:964, 1954.
41. Bangham, D.R., "The Transmission of Homologous Serum Proteins to the Fetus
and to the Amniotic Fluid in the Rhesus Monkey," J. Physiol. (London),
153:265, 1961. , . ;.
42. Rhoades, M.M. , "Meiotic Behavior of Chromosomes," in The Cell, Vol. 3,
Brachet J. and Mirsky, A., eds. New York Academic Press, 1961, p. 11.
43. Burnham, C.R., Discussions in Cytogenetics, Minneapolis, Minn.: Burgess
Publishing Co. , 1962, p. 20.
44. Stern, H. and Hotta, Y., "Biochemical Controls of Meiosis," in Annual
Review of Genetics, Vol. 7, Roman, H.L., ed, Palo Alto, Calif.: Annual
Reviews Inc., 1973, p. 37.
15-115
REFERENCES (Continued)
45. Hsu, T.C. and Benirshke, K. , eds , An Atlas of Mammalian Chromosomes,
Vols. 1-6, New York: Springer-Verlag, 1967-1971.
46. Vickers, A.D., "Amniotic Sex Chromatin and Foetal Sexing in the Mouse,
J. Reprod. Pert. 14:503, 1967.
47. Cassady, G. and Cailliteau, J., "The Amniotic Fluid in Anencephaly , " Am. J.
Obst. & Gyn. 97:395, 1966.
48. Lee, T.Y. and Wei, P.Y., "Spectrophotometric Screening of Amniotic Fluid
in Anencephalic Pregnancies," Am. J. Obst. & Gyn. 107:917, 1970.
49. Emery, A.E.H., "Biochemical Analysis of Amniotic Fluid," in Antenatal
Diagnosis of Genetic Disease, Emery, A.E.H., ed, Baltimore: The Williams
and Wilkins Co., 1973, p. 113.
50. Liley, A.W., "Errors in the Assessment of Hemolytic Disease from Amniotic
Fluid," Am. J. Obst. S Gyn. 86:485, 1961.
51. Grimes, L.D. and Cassady, G. , "Fetal Gastrointestinal Obstruction: Prenatal
Diagnosis Based on Amniotic Fluid Analysis," Am. J. Obst. & Gyn. 106:1196,
1970.
52. Emery, A.E.H.; Eccleston, D. ; Scrimgeour, J.B.; and Johnstone, M. , "Amniotic
Fluid Composition in Central Nervous System Malformations," J. Obst. S
Gyn. Br. Comm. 79:154, 1972.
53. Maori, J.N., Josii, M.S., and Evans, M.I., "An Antenatal Diagnosis of Spina
Bifida in the Lewis Rat," Nature (New Biol.), 246:89, 1973.
54. Peterson, E.N.; Hutchinson, D.L.; Sagbagha, R.E.; Royal, J.S.; and
Levitt, M.J., "Sonography and Amniocentesis as Predictors of Gestational
Age and Fetal Growth in the ly-iesus Monkey," Am. J. Obstet. Gynecol.
114 (No. 7) :883, 1972.
15-116
Isoimmunization
It became apparent soon after Rh incompatibility was postulated to be
responsible for the hydrops, anemia, jaundice, and brain damage associated with
the disease process designated erythroblastosis that methods of early detection
were the only possible means to predict the probability of disease in these
fetuses. Tests to assess the presence of Rh antibodies in the circulation of
the sensitized gravid female, and the presence and quantity of fetal erythrocytes
in the maternal circulation led to the development of prompt exchange transfu-
sions for neonates with erythroblastosis fetalis.
The principle method of early detection of Rh hemolytic disease of the
fetus in utero is based on the detection of biliriibin in amniotic fluid. It was
shown that in the fetus, high levels of bilirubin pigment in the amniotic fluid
correlate with the severity of the hemolytic disease in utero. Therefore, many
of the animal models pertaining to erythroblastosis involve various aspects of
bilirubin metabolism. Guinea pigs, rats, and rhesus monkeys were used in these
studies. A study in guinea pigs i demonstrated a bidirectional transfer of radio-
active carbon labeled unconjugated bilirubin across the placenta from the fetal
to maternal side and vice versa. Conjugated bilirubin injected into the fetal
circulation demonstrated only trivial passage of the conjugated pigment into the
maternal circulation. A later study ^ using radioactive tagged conjugated bili-
rubin and labeled water soluble BSP demonstrated that high molecular weight water
soluble substances do not diffuse readily across the placental membrane. Similar
studies of bilirubin disposition in fetal monkeys ^' "■ ^' ^ supported the results
previously obtained in guinea pigs. These data suggest that in both guinea pigs
and primates, the placenta is virtually impermeable to conjugated bilirubin and
that both the monkey and guinea pig fetuses may exhibit an impairment of hepatic
excretion of conjugated bilirubin. In both the guinea pig and monkey, unconju-
gated bilirubin readily entered amniotic fluid from the maternal but not the
fetal circulation. In contrast to the results of the studies in the guinea pig
and monkey, investigations using tritiated bilirubin in rats' were unable to
demonstrate transfer of unconjugated bilirubin from fetus to mother. While these
differences may be due to species variability, it is evident that there is a need
for further data on the disposition of bilirubin especially in primates. The
correspondence of greater concentrations of bilirubin pigments to progressive
severity of in utero fetal involvement of the human have led to the use of
(A A450) spectrophotometric studies of human amniotic fluid in the management of
Rh isoimmunization.*'® The fact that bilirubin pigment concentrations in amni-
otic fluid follow increased sensitization of the Rh{D)~ mother as reflected by
rising antibody titres in her circulation, would seem to indicate that the
maternal-fetal distribution of bilirubin in the human closely approximates that
which was later demonstrated to exist in the monkey and guinea pig.
Some clinical symptoms associated with hemolytic disease of the newborn,
namely jaundice, failure to thrive and positive Coombs test, were reported in
consecutive litters of piglets from a sow mated to a boar with incompatible
antigens associated with his red cells. Although some clinical signs of hemo-
lytic disease were present in these piglets, the pig is not a true model for
human hemolytic disease, because there is no in utero involvement of the fetuses.
15-117
Involvement of the piglets only occurs if during the suckling period they are
exposed to the maternal antibodies contained in the collostrum.^°
An animal model which is useful in studying methods of treatment for the
jaundice of hemolytic disease is a genetic strain of rat (j/j) which is bred to
carry a recessive genetic disorder of hyperbilirubinemia. ^^ This type of muta-
tion in the rat was initially described by Gunn.'^ As a consequence of the
demonstration by Haddock and Nadler-'-' that bilirubin toxicity is modified by
blue light treatment in cultures of human fibroblasts, hyperbilirubinemic j/j
rats have shown less neural injury when exposed to blue light. !*• i^- ^^ The
photodecomposition of bilirubin has also been successfully used in human new-
borns who are at risk for central nervous system damage due to bilirubin toxicity
from a variety of causes .!''■ i^' ^^
In the case of severe in utero involvement of the fetus, it has often
been necessary to carry out intrauterine transfusion of the human fetus. As
early as 1922, experiments with uptake of India ink from the peritoneal cavity
to the circulating blood by lymphatic channels were carried out on fetal kittens
by Cunningham. ^° He found that the entry of material into mediastinal lymph
nodes only occurred in association with respiratory activity which he observed
in older fetuses. Since then the validity of his assumption from this model has
been confirmed and the role of diaphragmatic movement in accelerating the rate
of absorption of particulate matter (i.e., red cells) from the peritoneal cavity
has been established. ^■' Thus it was postulated that uptake of blood might be
slow and less efficient in the fetus owing to the absence of respiratory activity
under normal intrauterine conditions. In recent years,, further interest in the
mechanism and fate of red cells transfused by the intraperitoneal route to the
fetus in utero has been stimulated by its use for administration of blood to the
human fetus in severe erythroblastosis fetalis. Pritchard and VJeisman^^ had
determined the usefulness of absorption of erythrocytes from the peritoneal
cavity of humans in 1957. In 1967, the use of the fetal lamb as a model gave
retrospective confirmation to the relative efficiency of this method of adminis-
tering red blood cells. ^^ The results obtained from the experiments in the fetal
lamb support the contention that, in the human fetus, the majority of red cells
administered by the intraperitoneal route reach the fetal circulation intact.
Thus uptake of at least 80 percent of the labeled cells by the fetal lamb is in
close agreement with the data obtained by Taylor et al., in 1966, using tagged
adult red cells injected into the peritoneal cavity of two erythroblastotic human
fetuses. The total uptake of donor blood was calculated to be as high as 93 per-
cent in one fetus and 77 percent in the other.
Information is now accumulating that marked isoantigen differentiation
is a feature of various species of animal as well as of man.^*'^^'^® By use of
the isoimmunization method, antigens have been detected in the red blood cells
of chimpanzees, gibbons, yellow baboons, hamadrayas baboons, mandrills, rhesus
monkeys, and marmosets. Of these the hamadrayas baboon ^^ appears to be most
promising for use in developing a model of hemolytic disease of the newborn and
in devising a method of antenatal treatment of that disease. Although use of
anti-Rh serum is preventing onset of sensitization in hiimans , it is still neces-
sary to look for new methods of devising ways of protecting the rhesus-positive
fetuses of rhesus-negative women who are presensitized through a variety of
mechanisms. Verbickij presents data that indicate success in setting up a
breeding colony of hamadrayas baboons that represent a sufficiently faithful
model of hemolytic disease of the newborn in man. The author failed to find
complete parallelism between the titre of isoimmune antierythrocyte antibodies
in the blood of the female baboon and the severity of the disease in the fetus.
However, the model is sufficiently similar to that of man that he has been able
to devise new methods of antenatal treatment of the disease (at least in the
model system) . The method devised by Verbickij is based on the principle of
forming a barrier in the amniotic fluid consisting of haptenes which bind mater-
nal isoimmune antibodies and thus do not allow them to penetrate to the eryth-
rocytes and fixed cells of the fetal tissues and organs. The author used
erythrophosphatides isolated from the blood of hamadrayas baboons of correspond-
ing phenotype as haptene. This model holds promise for use in the human situa-
tion; however, its usefulness in the human can never be brought about without
biochemical definition of human haptene and controlled experimental use of the
haptene-binding technique in Rh-sensitized pregnant women.
In summary, the availability of animal models and their applicability as
models in the various phases of this research has been considered. During the
course of the research which led to the ultimate prevention of erythroblastosis
fetalis a number of animal models were considered based on several criteria.^*
(1) Dog - availability, breeding ease, gestational period and the
existence of canine erythroblastosis.
(2) Rodent species (rat, guinea pig, mouse, rabbit) - availability,
breeding ease, and inducibility of hemolytic disease.
(3) Donkey or mule - large size of fetus and presence of pathologic
erythroblastosis manifestations.
(4) Primates (chimpanzee and baboon) - system of comparable blood
group isoantigens and isoimmune hemolytic disease.
These models were employed in selected phases of the research but ulti-
mately rejected as models for Rh isoimmune hemolytic disease in humans for the
following reasons : ^^' ^^
(1) Dog - dissimilar placental construction compared to humans,
there is no placental transfer of antibodies.
(2) Rodent species - small fetal size was prohibitive for surgi-
cal procedures comparable to human situation and disease
manifestations were highly variable even within the same
litter.
(3) Donkey or mule - disease pathology is similar but there is.
no placental transfer of antibodies.
Primates - the advent of intense research on the isoantigens
of primates and the mechanism of isoimmune disease in these
animals is a recent event. Although these animals may ulti-
mately prove to be good models for the study of isoimmune
hemolytic diseases similar to erythroblastosis fetalis, the
availability of the primate species, cost, and a lack of
knowledge of the blood group isoantigens in these species did
not make them ideal models for the type of research required
to rapidly solve the Rh problem.
15-120
REFERENCES
1. Schenker, S., Dawber, N.H., et al. , J. Clin. Invest. 43:32, 1964.
2. Schenker, S., Goldstein, J., et al., Amer J. Physiol. 208:553, 1965.
3. Lester, R. Behrman, R.E., et al. , Pediatrics 32:416, 1963.
4. Lester, R. , and Schmid, R. , J. Clin. Invest. 42:736, 1963.
5. Lucey, J.F., Behrman, R.E., et al., Amer. J. Dis. Child. 106:350, 1963.
6. Schenker, S., Bashore, R.A. , et al., "Bilirubin Disposition in Foetal Monkeys,''
in Bilirubin Metabolism, I.A.D. Boucher and B.H. Billing, (eds.) Blackwell
Scientific Publications, 1966, p. 199.
7. Grodsky, G.M. , Contopoulos, A.N. , et al., Amer. J. Physiol. 204:837, 1963.
8. Misenheimer, H.R. , "Role of Amniotic Fluid Studies (A A450) in the Management
of Rh Immunization," in Amniotic Fluid, S. Natelson and A. Scommegna, (eds.)
New York: John Wiley and Sons, 1974, p. 171.
9. Charles, A.G., "The Rh Problem and Amniotic Fluid," in Amniotic Fluid, S.
Natelson and A. Scommegna, (eds.) New York; John Wiley and Sons, 1974,
p. 179.
10. Hall, S.A. , Rest, J.R. , et al., "Concurrent Haemolytic Disease of the Newborn
and Thrombocytopenic Purpura in Piglets Without Artificial Immunization of
the Dam," Vet. Rec. 91 (No. 27):677, 1972.
11. Swarm, R.L., "Congenital Hyperbilirubinemia in the Rat: An Animal Model for
the Study of Hyperbilirubinemia," in Animal Models for Biomedical Research,
Vol. 4, Natl. Acad. Sci., Washington, D.C. , 1971, p. 149.
12. Gunn, C.H., "Hereditary Acholuric Jaundice in New Mutant Strain of Rat,"
J. Hered. 29:137, 1938.
13. Haddock, J.H., and Nadler, H.L., "Bilirubin Toxicity in Human Cultivated
Fibroblasts and Its Modification by Light Treatment," Proc. Soc. Exp. Biol.
Med. 134:45, 1970.
14. Johnson, L. , and Shutta, H.S., "Quantitative Assessment of the Effects of
Light Treatment in Infant Gunn Rats," in Bilirubin Metabolism in the
Newborn, D. Bergsma and D. Hsia (eds.), Baltimore: Williams and Wilkins,
1970, p. 114.
15. Ostrow, J.D., and Branham, R.V. , "Photodecomposition of Bilirubin and
Biliverdin In Vitro," Gasteroenterology 58:15, 1970.
15-121
16. Ostrow, J.D., and Branham, R.V. , "Photodecay of Biliriibin In vitro and in
the Jaundiced (Gunn) Rat," in Bilirubin Metabolism in the Newborn,
D. Bergsma, and D. Hsia, (eds.) Baltimore: Williams and Wilkins Co.,
1970, p. 93.
17. Bergsma, D. and Hsia, D. , "Bilirubin Metabolism in the Newborn" in Original
Birth Defects Series, Vol. 6, Baltimore: Williams and Wilkins Co., 1970,
p. 136.
18. Behrman, R.E. and Hsia, D. , "Summary of a Symposium on Phototherapy for
Hyperbilirubinemia," Fetal Neonatal Med. 75:718, 1970.
19. Karon, M. , Imach, D. , et al., "Effective Phototherapy in Congenital
Nonobstructive Nonhemolytic Jaundice," N. Eng . J. Med. 282:377, 1970.
20. Cunningham, R.S., "Studies in Absorption from Serous Cavities. V. The
Absorption of Particulate Matter from the Peritoneal Cavity of the Fetus,"
Amer. J. Physiol. 62:253, 1922.
21. Morris, B. , "The Effect of Diaphragmatic Movement on the Absorption of
Protein and of Red Cells from the Peritoneal Cavity," Austral. J. Exp. Med.
80:77, 1953.
22. Towell, M.E. , Gregg, J.R. , et al., "Intraperitoneal Blood Transfusion in
the Fetal Lamb," in Diagnosis and Treatment of Foetal Disorders , K.
Adamsons (ed.) p. 272 (Reference incomplete as to publication and date).
23. Pritchard, J.A. , and Weisman, R. , "The Absorption of Labeled Erythrocytes
from the Peritoneal Cavity of Humans," J. Lab. Clin. Med. 49:736, 1957.
24. Stone, W.H., and Irwin, M.R. , Advances in Immunol. 3:315, 1963.
25. Tihonov, V.N. , "Genetic Systems of Animal Blood Groups," (Russian)
Novosibirsk, 1966.
26. Verbicki j , M.S., "Study of Haemolytic Disease of the Newborn in Experiments
on Rats (Russian)," Thesis for Candidate Degree, Moscow, 1964.
27. Verbickij, M.S., "The Use of Hamadrayas Baboons for the Study of the
Immunological Aspects of Human Reproduction," Acta Endocrinol (Suppl)
166:492, 1972.
28. Charles, A.G., ed., Rh Isoimmunization and Erythroblastosis Fetalis,
New York: Appleton-Century Crofts, 1969.
29. Diamond, L.K. - Interview.
Respiratory Distress Syndrome
The report on the respiratory distress syndrome traces the understanding
of RDS from its early stages to the present knowledge of the diagnosis and treat-
ment. From the historiograph, it can be seen that the present-day understanding
of the disease and its treatment evolved through several stages which we identify
as follows:
(1) Understanding the role of surfactant
(2) Composition of surfactant
(3) Elucidation of biosynthetic pathways
(4) Stages of fetal lung development
(5) Effect of glucocorticoids on lung development.
In each of these areas of research activity, animal models played a significant
role in the development of the present-day knowledge of RDS. In most of these
areas, the animal studies have been very extensive, and it is not the intent of
this report to assemble a detailed review of the work. Rather, we shall examine
the role of animal models in several of the significant advances made during the
last several years. We shall address the question of the usefulness of the ani-
mal models and where the animal models failed with respect to their relevance to
the human.
Role of Surfactant . :
The early work in elucidating the role of surfactants in lung mechanics
was done almost entirely with animal models. In fact, most of the work cannot
justifiably be designated as work with animal models in that it was done with
excised lungs taken from animals, and in some cases from man. In the first
paper identified in the historiograph,'' von Neergaard used lungs excised from
dog, pig, and man to measure surface/volume relationships. The next significant
work, that of Pattle in 1955,^ lung washes were obtained from both excised animal
lungs in vivo to show the presence of surfactant in these washes. The studies
of Clements ^"^ on the relationship of the pressure/volume curves of lungs to the
surface tension properties of lung extracts were performed mainly with excised
dog lungs.
It should be pointed out, however, that the key work which related the
respiratory distress syndrome to lack of surfactant was not performed with ani-
mal models but with autopsy specimens obtained from humans.® The question of
whether animal models could have been used in this discovery is not relevant
since pathology specimens were used. Once the relationship between RDS and lack
of pulmonary surfactant was made, then the role of animal models in understanding
pulmonary surfactant synthesis became important.
15-123
Surfactant Composition
As in the case of establishment of the importance of pulmonary surfactant
for lung stability, studies on the composition of the surfactant were performed
mainly on excised animal tissue or autopsy specimens from humans. The early
work of Klaus ' utilized beef lung for the determination of the composition and
properties of the pulmonary surfactant. Similarly, the work of King and asso-
ciates ^"'° was based on the analysis of extracts from excised dog lung. A recent
report by Clements ^^ sumiriarizing the current state of knowledge in the overall
composition of lung surfactant is based mainly on data obtained from dog lung
but states that the overall composition is quite similar for most mammalian
species.
Biosynthetic Pathways for Fetal Lung Development
The study of the process of lung maturation and the biosynthetic pathways
of phospholipid synthesis relied heavily upon animal model experimentation. It
should be pointed out that through the course of the investigations, frequent
cross comparisons were made with humans, most of which were taken from autopsy
specimens. The work by Klaus and co-workers-'^ which linked the mitochondrial
of Type II alveolar cells to the secretion of phospholipids was performed with
guinea pigs. The work of Buckingham and Avery i^ showing that the appearance of
phospholipids in lung extracts was linked to the appearance of inclusion bodies
in Type II alveolar epithelial cells was performed with mice.
Studies on the biosynthetic pathways for synthesis of phospholipids have
centered mainly upon lecithin biosynthesis since this is the main constituent
of the surface-active material. Two pathways for biosynthesis of lecithin have
been identified in mammalian species, and these are designated as the choline
incorporation pathway in which CDP choline reacts with a diglyceride to form
lecithin. In the second pathway, ethanol amine is phosphorylated, activated,
and linked to diglyceride to form phosphotityl ethanol amine. This is then
successively methylated to ultimately form lecithin. As indicated in the report,
a great deal of experimental work has been performed on elucidating the biosyn-
thetic pathways for lecithin production in fetal lungs. In a series of papers,
Gluck and co-workers investigated the biosynthetic pathways using rabbit and
sheep animal models. ^""^^ Gluck 's subsequent studies showed that the biosyn-
thetic pathways in the sheep and rabbit were different from those in the rhesus
and human fetus. ^' The biosynthetic pathways of lecithin in the human have been
elucidated in a series of papers by Zachman.^^
It should be pointed out that the animal models possess a distinct advan-
tage in determining biosynthetic pathways in that radioactive precursors can be
utilized in these studies. This enables the investigator to follow directly the
pathway of a particular compound through several synthetic steps. In human stud-
ies, pathways must be elucidated indirectly. Recently, the rhesus monkey has
been shown to be a good animal model for studying fetal lung development and the
biosynthesis of lecithin. The group of Farrell and Epstein, using rhesus monkey
fetuses, both in vitro and in vivo, followed the synthesis of lecithin using
15-124
radioactively labeled precursors. ^^'^^ They found that the first pathway
(choline incorporation) was responsible for almost all of the lecithin synthe-
sized by the lung tissue. An abrupt increase in the activity of this pathway
occurred at the time when gestation was 90 percent complete. This increase in
the Path I activity allows a surge in total lung lecithin and furthermore corre-
lates significantly with the rise in amniotic fluid lecithin. ^^
The historiograph in the report identified the work of Gluck in 1971 as
being a critically important factor in the present-day medical armamentariiim
against RDS . In this work, Gluck and co-workers studied phospholipid levels in
amniotic fluid from 302 amniocenteses and showed that these levels reflect those
in the lung of the developing fetus. Comparing the lecithin concentration to
the sphingomyelin concentration, a ratio can be obtained and Gluck' s results
showed that a sharp increase in this ratio occurred at 35 weeks of gestation.
Determination of the lecithin/sphingomyelin (L/S) ratio was shown to be diagnos-
tic of the state of pulmonary development of the fetus and thus could have a
predictive value of the likelihood of RDS occurring. This work was based on the
suggestion of Scarpelli in 1957^* who studied tracheal and amniotic fluid phos-
pholipids in sheep and suggested that the lung was the source of amniotic fluid
phospholipids. Gluck 's amniocenteses were performed in women with normal preg-
nancies. At that time, a human study seemed indicated because the relevancy of
the abnormal model was not established until later. Gluck and co-workers made
several assumptions about biosynthetic pathways in humans based upon indirect
evidence obtained from the composition of the fatty ester composition of lecithin
samples. These are in disagreement with the above-cited studies in the rhesus
monkey in which the pathways were obtained directly to radioisotope study. From
a pragmatic point of view, however, the human studies were necessary at the time
Gluck performed them to demonstrate that one could accurately assess the maturity
of the fetal pulmonary system before birth.
Effect of Glucocorticoids on Lung Development
One of the most significant developments in RDS therapy is the antenatal
treatment of the fetus through administration of steroids to the mother to stimu-
late pulmonary development of the fetus in utero. The historical developments
for this treatment are outlined in the report and will not be discussed in detail
here. The history of this development represents a rich interplay between animal
models and studies in humans. Basis for the development was the demonstration
in 1953 that cortisone induced certain enzymes in the intestines of fetal rats.^^
The experimental demonstration of the stimulatory effect of steroids upon lung
tissue was performed in 1969 by Liggins ^^ who showed that the administration of
steroids to fetal lambs resulted in premature parturition and accelerated lung
maturation. In 1970, DeLemos ^' administered Cortisol to fetal lambs and demon-
strated increased surfactant production in the treated animals. The effect of
corticoids in general on fetal lung maturation was subsequently confirmed in
lambs, rabbits, and rats. 28-32
The clinical study in 1972 by Liggins was based on the animal studies
showing the stimulatory effect of steroids on lung maturation in the developing
fetus. More importantly, his mode of treatment was based on a clinical study
15-125
in 1961 by Migeon-^^ which showed that Cortisol administered to mothers at mid-
pregnancy crossed the placenta from mother to fetus. An estimation of the
probable safety of administration of Cortisol to the mother was based upon fur-
ther clinical studies performed in 1966 and 1957 s". 35 which studied the effects
of steroid therapy during pregnancy.
The animal model studies which led to Liggins' work demonstrated the
efficacy of steroid administration in promoting lung maturation but were inade-
quate because steroids administered to the mother did not cross the placental
barrier in the sheep. Human studies were essential at this point to determine
whether or not lung maturation could be stimulated in infants with a high risk
of developing RDS. It should be emphasized at this point that the administration
of steroids must still be considered as an experimental rather than an accepted
clinical practice.
After Liggins' initial clinical demonstration of the stimulatory effects
of steroids in humans, animal studies on the mechanism of steroid stimulation
continued. Ballard and Ballard in 1972 ^^ showed that fetal lung tissue of sev-
eral species contained glucocorticoid receptor sites. This was followed by work
in 1974 3^ which showed receptor activity for glucocorticoids in lungs of human
fetuses and neonates.
The effect of glucocorticoid administration to the mother on the amniotic
L/S ratio in humans was studied in 1973 by Spellacy.ss These clinical studies
showed that the L/S ratio increased after a glucocorticoid was administered to
the mother. In another clinical study reported in 1975,^9 the levels of amni-
otic fluid Cortisol with relation to gestational age was measured. The results
showed that a sharp increase in the Cortisol levels occurred after the 34th week
of gestation. This increase in Cortisol corresponds to the increase in lecithin
content of the amniotic fluid. The relevance of the rhesus monkey as a model
for human lung development was recently demonstrated in a report by Gluck.*°
He shows that the biochemical pathways for surfactant are the same and the rise
in L/S ratios corresponds to those found in the human. The relevance of the
rhesus as an animal model will be important in future studies on the safety and
efficacy of the antenatal administration of steroids.
Conclusions
We believe the results show that both animal and human studies were essen-
tial in the present-day status of prevention and therapy of RDS. In particular,
two clinical studies were essential for this development. These are the study
of Gluck in 1971 showing the predictive value of the L/S ratio and the clinical
study of Liggins in 1972 showing the stimulatory effect of antepartum glucocor-
ticoid administration. Relevant animal models had not been demonstrated at the
time of these studies, and thus clinical studies were a logical, essential step.
In a larger sense, in any therapeutic procedure, the time comes when a human
study must be undertaken if the technique is to find use in the human. It
appears from our study of RDS that the clinical trials cited above came at an
appropriate time in the development of the diagnostic and therapeutic procedures.
REFERENCES
1. von Neergaard, K. , "Neue Auffassungen Uber Eien Grundbegrif f der Atemmechanik.
Die Retraktionskraft der Lunge, Abhangig von der Oberf lachenspannung in den
Alveolen," Z. Ges . Exp. Med. 66:373, 1929.
2. Pattle, R.E., "Properties, Function, and Origin of the Alveolar Lining
Layer," Nature 175:1125, 1955.
3. Clements, J.A. , "Surface Tension of Lung Extracts," Proc. Soc. Exp. Biol.
in Med. 95:170, 1957.
4. Clements, J.A. , Brown, E.S., and Johnson, R.P., "Pulmonary Surface Tension
and the Mucous Lining of the Lungs: Some Theoretical Considerations,"
J. Appl. Physiol. 12:262, 1958.
5. Clements, J. A.; Hustead, R.F.; Johnson, R.P.; and Gribetz, I., J. Appl.
Physiol. 16:444, 1961.
6. Avery, M.E. and Mead, J., "Surface Properties in Relation to Atelectasis
and Hyaline Membrane Disease," Am. J. Dis . Child. 97:517, 1959.
7. Klaus, M.H., Clements, J.A. , and Havel, R.J., "Composition of Surface-Active
Material Isolated from Beef Lung," Proc. Nat. Acad. Sci . 47:1858, 1961.
8. King, R.J.; Klass , D.J.; Gikas, E.G.; and Clements, J.A. , "Isolation of
Apoproteins from Canine Surface-Active Material," Am. J. Physiol. 224:788,
1973.
9. King, R.J. and Clements, J.A., "Surface-Active Material from Dog Lung.
I. Method of Isolation," Am. J. Physiol. 223:707, 1972.
10. King, R.J. and Clements, J.A., "Surface-Active Materials from Dog Lungs.
II. Composition and Physiological Correlations," Am. J. Physiol. 223:715,
1972. ... -
11. Clements, J.A. , "Composition and Properties of Pulmonary Surfactant,"
Respiratory Distress Syndrome, C.A. Villee, D.B. Villee, and J. Zuckerman,
editors. New York: Academic Press, 1973, p. 77.
12. Klaus, M. ; Reiss, O.K.; Tooley, B.H.; Peil, C. ; Clements, J.A. , Science
137:715, 1962.
13. Buckingham, S. and Avery, M.E., "Time of Appearance of Lung Surfactant in
the Fetal Mouse," Nature 193:688, 1962.
14. Gluck, L. ; Motoyama, E.K.; Smitz, H.L.; and Kulovich, M.V., "The Biochemical
Development of Surface Activity in Mammalian Lung," Ped. Res. 1:237, 1967.
15-127
REFERENCES (Continued)
15. Gluck, L. , Sribney, M. , and Kulovich, M.V., "The Biochemical Development
of the Surface Activity in Mammalian Lung. Part II," Ped. Res. 1:247,
1967.
16. Gluck, L. , Landowne, R.A. , and Kulovich, M.V. , "Biochemical Development of
Surface Activity in Mammalian Lung. Part II. Structural Changes in Lung
Lecithin During Development of the Rabbit Fetus and Newborn," Ped. Res.
4:352, 1970.
17. Gluck, L. ; Kulovich, M.V. ; Eidelman, A.I.; Cordero, L. ; and Khatin, A.F.,
"Biochemical Development of Surface Activity in Mammalian Lung. Part IV.
Pulmonary Lecithin Synthesis in the Human Fetus and Newborn and Etiology
of Respiratory Distress Syndrome," Ped. Res. 6:81, 1972.
18. Zachman, R.D., "The Enzymes of Lecithin Biosynthesis in Human Newborn Lungs.
III. Phorphorylcholine Glyceride Transferase," Ped. Res. 7:632, 1973.
19. Epstein, M.F., Farrell, P.M., and Chez, R.A., "Lung Lecithin Synthesis in
Primates," in Advances in Primatology , E.I. Goldsmith and J. Moor-
Jankowski, editors. New York: Plenum Press, in press 1975.
20. Farrell, P.M. and Epstein, M.F., "Lecithin Synthesis in the Fetal and Neonatal
Primate Lung as Measured in Vitro," Ped. Res. 8:356, 1974.
21. Farrell, P.M.; Epstein, M.F.; Fleischman, A.R. ; Oakes, G.K.; and Knight, E. ,
"Lecithin Synthesis in Fetal Primate Tissues as Measured in Vivo," Ped.
Res. 8:446, 1974.
22. Epstein, M.F. , Farrell, P.M., and Willison, J., "Correlation of Fetal Lecithin
Synthesis and the Amniotic Fluid L/S Ratio," Ped. Res. in press 1975.
23. Gluck, L.; Kulovich, M. ; Borer, R. ; Brenner, P.H.; Anderson, G.G.; and
Spellacy, W.N., "Diagnosis of the Respiratory Distress Syndrome by Amnio-
centesis," Am. J. Ob. Gyn. 109:440, 1971.
24. Scarpelli, E.M., "The Lung Tracheal Fluid and Lipid Metabolism of the Fetus,"
Ped. 40:951, 1967.
25. Moog, F., "The Influence of the Pituitary-Adrenal System on the Differen-
tiation of Phosphatase in the Duodenum of the Suckling Mouse," J. Exptl.
Zool. 124:329, 1953.
26. Liggins, G.C., "Premature Delivery of Foetal Lambs Infused with Glucocorti-
coids," J. Endocrin. 45:515, 1969.
27. DeLemos, R.A. ; Shermata, D.W. ; Knelson, J.H. ; Kotas, R. ; and Avery, M.E.,
"Acceleration of Appearance of Pulmonary Surfactant in the Fetal Lamb by
Administration of Corticosteroids," Am. Rev. Resp. Dis. 102:459, 1970.
REFERENCES (Continued)
28. Kikkawa, Y. ; Kaibara, M. ; Motoyama, E.K.; Orzalesi, M.M. ; and Cook, CD.,
"Morphologic Development of Fetal Rabbit Lung and Its Acceleration with
Cortisol," Am. J. Path. 64:423, 1971.
29. Knelson, J.H. , "Environmental Influence on Intrauterine Lung Development,"
Arch. Intern. Med. 127:421, 1971.
30. Kotas, R.V. and Avery, M.E., "Accelerated Appearance of Pulmonary Surfactant
in the Fetal Rabbit," J. Appl . Physiol. 30:358, 1971.
31. Kotas, R.V.; Fletcher, B.D.; Torday , J.; and Avery, M.E., "Evidence for
Independent Regulators of Organ Maturation in Fetal Rabbits," Ped. 47:57,
1971.
32. Motoyama, E.K. ; Orzalesi, M.M.; Kikkawa, Y. ; Kaibara, M. ; Wu, B.; Zigas , C.J.;
and Cook, CD., "Effect of Cortisol on the Maturation of Fetal Rabbit
Lungs," Ped. 48:547, 1971.
33. Migeon, C.J., Bertrand, J., and Gemzell, CA. , "The Transplacental Passage of
Various Steroid Hormones in Mid-Pregnancy," Rec. Prog. Horm. Res. 17:207,
1961.
34. Yackel, D.B., Kempers , R.D., and McConahey, W.M. , "Adenocorticosteroid
Therapy in Pregnancy," Am. J. Ob. Gyn. 96:985, 1966.
35. Walsh. S.D. and Clark, F.R. , "Pregnancy in Patients on Long-Term Corticos-
teroid Therapy," Scot. Med. J. 12:302, 1967.
36. Ballard, P.L. and Ballard, R.A. , "Glucocorticoid Receptors and the Role of
Glucocorticoids in Fetal Lung Development," Proc. Natl. Acad. Sci. 69:2668,
1972.
37. Ballard, P.L. and Ballard, R.A., "Cytoplasmic Receptor for Glucocorticoids
in Lung of the Hirnian Fetus and Neonate," J. Clin. Invest. 53:477, 1974.
38. Spellacy, W.N.; Buhi, W.C; Riggall, F.C ; and Holsinger, K.L., "Human
Amniotic Fluid Lecithin/Sphingomyelin Ratio Changes with Estrogen or
Glucocorticoid Treatment," Am. J. Ob. Gyn. 115:216, 1973.
39. Fencl, M. and Tulchinsky, D. , "Total Cortisol in Amniotic Fluid and Fetal
Lung Maturation," New Eng. J. Med. 292 (No. 3):133, 1975.
40. Gluck, L. ; Chez, R.A.; Kulovich, M. ; Hutchinson, D.L.; and Niemann, W.H. ,
"Comparison of Phospholipid Indicators of Fetal Lung Maturity in Amniotic
Fluid of Monkey (Macaca mulatta) and Baboon (Papio papio)," Am. J. Ob.
Gyn. 230:524, 1974.
15-129
GLOSSARY
A- Antigen. A substance, or blood factor, on the surface of some individuals'
red cells, that provokes an immune reaction from anti-A antibody.
ABO blood groups . See human blood groups.
ABO-Compatible . One person is ABO-compatible to another if his red cells do not
carry A or B antigen that will provoke a reaction from antibodies in the
other's serum.
ABO-Incompatible . One person is ABO-incompatible to another if his red cells
carry A and/or B antigen that will provoke an immune reaction if transfused
into the other, due to the presence in the other's serum of anti-A and/or
anti-B antibody.
ABO protection. The immunologic phenomenon through which a fetus that is ABO-
incompatible with its mother as well as Rh- incompatible with her appears to
be less in danger of erythroblastosis than one which is Rh- incompatible but
ABO-compatible with her.
Agglutinate (verb) . To bring together in an aggregate, or clump, as some anti-
bodies do to red cells.
Agglutination. Immune reaction in which red cells carrying a specific antigen
(for example. A) are stuck together in clumps, or aggregates, by the corre-
sponding antibody (anti-A) .
Alveoli (pulmonary) . Small sac-like structures through the walls of which gas
exchange takes place.
Amniocentesis . Passage of a hollow needle into the amniotic fluid that surrounds
the fetus in the womb, and the removal of a specimen of the fluid.
Amniotic fluid. Fluid within the amniotic sac surrounding the fetus.
Anemia. A deficiency state of blood in which there are too few red cells or the
red cells are of too poor quality to fulfill their oxygen-transporting func-
tion in the body.
Anencephalic. Congenital absence of the cranial vault with the brain partially
or completely missing.
Anti-A antibody. An antibody naturally present in individuals of groups 0 and
B that will attack and destroy red cells of persons in groups A and AB.
Anti-B antibody. An antibody naturally present in individuals of groups 0 and
A that will attack and destroy red cells of persons in groups B and AB.
Antibody . A substance produced by the body in response to a specific foreign
material, or antigen. An antibody acts, in an immune reaction, to defend the
body by destroying or nullifying the antigen against which it is made.
♦Adapted from Borland' s Illustrated Medical Dictionary , (Twenty-Fifth Edition) ,
W.B. Saunders Co. , Philadelphia, 1965; and Zimmerman, D.R. , Rh. The Intimate
History of a Disease and Its Conquest, Macmillan Publishing Co., Inc., New York,
1973.
15-131
Antigen. A substance on or in a red cell that is antagonistic to a human or
other organism in such a way that it forms an antibody against it. The blood
factors A, B, and Rh are antigens. Chemically, most antigens are proteins.
Anti-Rh antibody. An antibody that may be formed in Rh-negative individuals,
in response to antigenic challenge by the Rh factor, which will attack and
destroy red cells of persons who are Rh-positive.
Anti-Rh gamma globulin. See Rh vaccine.
Antitrypsin. A substance having an inhibitory action on the enzyme trypsin.
Ascites. Accumulation of serous fluid in the abdominal cavity, also called
hydrops .
Atelectasis. Incomplete expansion of the lungs at birth.
Autosome. Any ordinary paired chromosome as distinguished from a sex chromosome.
B-Antigen. A substance on the surface of some individuals' red cells that pro-
vokes an immune reaction from anti-B antibody.
Betamethasone . A synthetic glucocorticoid.
Bilirubin. A breakdown product of hemoglobin released when red cells are
destroyed; it is made by the liver. Some forms of this bile pigment are
highly toxic, and may stain and injure brain tissue (kernicterus) , causing
death.
Biopsy. The removal and examination of tissue from the living body.
Blood factor. An inherited antigen present on the surface membrane of red cells
of some individuals but not on others.
Blood groups. See human blood groups.
CPE. Alternative nomenclature for the Rh blood group system.
Challenge. In immunology, the administration of an antigen to awake an immuno-
logic response in a previously sensitized person.
Choline. A vitamin and basic constituent of lecithin.
Chromosome. A structure in the cell nucleus which transmits genetic information.
Compatibility. A person is compatible with another if his red cells can be
transfused into him without provoking an immune reaction, or transfusion reac-
tion.
Complement. A series of enzymatic proteins that interact and combine with the
antigen-antibody complex producing lysis when the antigen is an intact cell.
Complement fixation test. A test used to determine the presence of complement.
It is the basis of many serological tests for infection.
Congenital. Existing at or present before birth.
Cortices. Plural of cortex, the outer layer of a body structure. :'
Cortisol. A steroid hormone.
Cytodif f erentiation. In cells, to distinguish on the basis of differences or
to develop specialized form, character, or function.
Decidua. The mucous lining of the uterus thrown off after parturition.
Dexamethasone . A synthetic glucocorticoid.
ECG. Electrocardiogram - a graphic tracing of the electric current produced by
the excitation of the heart muscle.
Eclampsia. Convulsions and coma occurring in a pregnant woman. ■'-_,;■-,
Edema. Swelling of body tissues due to fluid retention.
Embryopathy. A morbid condition resulting from interference with normal embry-
onic development.
Encephalography . A graphic tracing of the potentials on the skull emanating from
nerve potentials in the brain.
Enzyme. A protein capable of producing or accelerating a change in (often a spe-
cific) compound.
Epidemiology. A study of the relationships of the various factors determining
the frequency and distribution of a disease.
Epitheliimi. The covering of the external and internal surfaces of the body
including the lining of vessels and other small cavities.
Ery thr oblast . An immature red cell. It is identifiable under the microscope
because, unlike adult red cells, it still retains a nucleus. Too rapid
destruction of adult red cells leads to compensatory overproduction of imma-
ture ones; hence, the disease name, erythroblastosis, which signifies the
presence of and excess of erythroblasts .
Erythroblastosis fetalis. Disease of fetal and early newborn life. Usually
occurs when red cells from Rh-positive fetus cross the placenta and provoke
immune response in Rh-negative mother. Her anti-Rh antibodies then enter
fetus, destroying its red cells, and stimulating abnormally high production
of immature red cells, or erythroblasts.
Erythrocyte. See red blood cell.
Etiology. The study or theory of the factors that cause disease and the method
of introduction to the host.
Exanthem. An eruptive disease or fever, a rash.
Exchange transfusion. In newborn erythroblastic infants, total or near-total
removal of the baby's Rh-positive blood, which is vulnerable to attack by
maternal antibodies brought from the womb, and its simultaneous replacement
with invulnerable Rh-negative blood.
Fetoscopy . Examination of the fetus by means of an endoscope inserted through
the abdomen.
Fibrin. An insoluble protein formed from fibrinogen during the normal clotting
of blood .
Fibrinogen. A soluble blood protein involved in the clotting process.
Fibroblast. A tissue connective cell.
Gamma globulin (GG) . That part of the serum of which antibodies are made. The
gamma globulin is separable into several parts on the basis of their molec-
ular weight. Two of these parts are designated 7S and 19S. ■ •
Genetics. The biologic science that deals with heredity, and change and simi-
larity between organisms through time.
Gestation. The period of development of the young until birth, the fetal period.
Glucocorticoid . Any corticoid that increases the rate of formation of carbohy-
drates from molecules such as proteins or fatty acids .
Gravid. Pregnant.
Group A. A person whose red cells carry the A antigen but not the B belongs to
group A.
Group AB. A person whose red cells carry the A antigen and the B antigen belongs
to group AB.
Group B. A person whose red cells carry the B antigen but not the A belongs to
group B.
Group 0. A person whose red cells carry neither the A antigen nor the B belongs
to group 0.
Hemagglutination. Agglutination of red blood cells. _ ~
Hemoglobin. The stuff of red cells, which gives them their color and which binds
oxygen so that the cells can transport it from the lungs to all body tissues.
Hemolysis. Destruction of a red cell by an agent that eats through its outer
membrane, spilling the contents. Some antibodies are hemolysins.
Hemolytic anemia. Anemia caused by the destruction of red cells. Antibody
against an antigen on a red cell's surface may hemolyze the cell. Erythro-
blastosis fetalis is a hemolytic anemia.
Herd immunity. When the number of immune members of a group is sufficient to
reduce greatly the spread of infection.
Hormone. A chemical produced in the body which has a specific regulatory func-
tion on the activity of an organ.
Human blood groups. Usually designates the four groups of individuals--A, B,
0, and AB — identified by the ABO system discovered by Landsteiner. For
clarity, other systems, like Rh, are said to define blood types, rather than
groups. Each blood group or type is based on a blood factor, or antigen, that
is present on its members' red cells.
Hyaline membrane. A layer of material lining the alveoli and alveolar ducts of
infants having respiratory distress syndrome - the membrane is composed of
fibrin.
Hydrops. The most severe form of erythroblastosis fetalis, in which the baby
is born waterlogged, swollen, and, usually, dead.
Hypoplastic. Marked by incomplete development of an organ.
Icterus. Yellowing of the skin. It occurs when excessive destruction of red
cells leads to a backup of their breakdown products in the body.
Icterus gravis neonatorum. A form of erythroblastosis found in newborns who are
unable to excrete bilirubin and other breakdown products of fetal cells
destroyed by anti-Rh antibody from the mother.
15-134
IgG antibody. One of the classes of antibodies (see antibody).
IgM antibody. One of the classes of antibodies (see antibody) .
Immune reaction. The self-protecting production of antibody against an antigen,
and the antibody's interaction with the antigen. Also called immune response.
Immunization. The formation by an individual of antibody against a particular
antigen. Once the individual has reacted immunologically to a given antigen,
he will respond, quickly, with antibody production whenever that antigen is
again present. This individual thus is immunized, or has developed an immu-
nity, to that antigen.
Immunology. The science that studies the immune reaction.
Incompatibility. A person is incompatible with another if his red cells will
provoke an immune reaction, or transfusion reaction, when transfused into the
other .
Intrapleural. Within the membrane lining the thoracic cavity.
Intrauterine transfusion. A transfusion of red cells into an erythroblastic
fetus, usually through a thin tube stuck through the mother's abdominal wall,
uterus, and into the fetal abdominal cavity.
In utero. In the uterus, e.g., a fetus.
In vitro. In glass, i.e., in a test tube or lab vessel rather than in a living
body (in vivo) .
Ischemic. Having a deficiency of the blood supply.
Isoantigen. An antigen that exists in alternate forms in a species and thus can
evoke an immune response in a member of that species lacking that form of
antigen.
Isoimmunization . Development of antibodies against an antigen derived from a
genetically dissimilar individual of the same species (see isoantigen) .
Jaundice. Yellowing of the skin. It occurs when excessive destruction of red
cells leads to a backup of their breakdown products in the body.
Kernicterus. Condition with severe neural symptoms associated with high levels
of bilirubin.
Kleihauer test. A laboratory method for identifying fetal red cells present in
a specimen of the mother's red cells. The hemoglobin of the adult cells is
washed away, while the hemoglobin in the fetal cells remains.
Lecithin. Any of a group of phospholipids found in animal tissues.
Lidocaine. A topical (local) anesthetic.
Lipids. A group of fatty substances including fatty acids, neutral fats, waxes, .
steroids, and phosphotides.
Lymphocyte. A white blood cell that plays a role in antibody production.
Mitochondria. Small spherical to rod-shaped particles in cells - principal site of
energy production - they are the portion of the cells with genetic continuity.
15-135
Mitotic. Pertaining to mitosis - a method of indirect division of a cell in which
the two daughter nuclei normally receive identical complements of chromosomes.
Mongolism. Down's syndrome - a genetic abnonnality in which the genetic material
of a chromosome (21) is triplicated instead of duplicated.
Myelinization. Formation of the lipid (myelin) sheath of certain nerve fibers.
Osmolality. A property of a solution which depends on the concentration of the
solute.
Parturition. The process of giving birth. "
Passive antibody. Antibody that has been injected into an individual, as contra-
distinct from active antibody, which is made by the individual's immune system
in response to an antigenic challenge.
Pathogenesis . Development of a morbid condition or disease - more specifically
on a cellular level.
Pathology. The science of disease and its causes. Pathologists conduct autop-
sies and render diagnoses on the basis of tests and analysis of specimens
removed from patients. In American hospitals, a pathologist often runs the
blood bank.
Pharyngeal. Pertaining to the pharynx - the membranous sac between the mouth
and nose and the esophagus.
Phospholipid. A lipid composed of fatty acids, glycerin, phosphate, and nitroge-
nous components .
Phototherapy. Use of blue light to lower bilirubin levels in the neonate. Bili-
rubin is susceptible to chemical breakdown when exposed to specific wave-
lengths of light.
Placenta. Tissue structure at the fetus' point of attachment to the uterine
wall. It is richly endowed with blood vessels. Maternal and fetal circula-
tions are separated by a very thin membrane, through which nourishment passes
into the fetus.
Plasma. The clear liquid portion of blood after the red cells have been removed.
Plasmin. A soluble blood protein derived from plasminogen - acts to lyse fibrin
clots (see plasminogen) .
Plasminogen. The blood soluble protein precursor of plasmin. ', .'.-;
Polyhydramnios . Excess of amniotic fluid.
Postpartum. After delivery of a baby. ^
Preeclampsia. A toxemia of late pregnancy. .. ,. ,
Prophylaxis . A prevention of disease, preventative treatment.
Protection. See ABO protection.
Proteolytic. Capable of splitting proteins by hydrolysis.
Red blood cells. Dish-shaped cells whose stuff, the hemoglobin, gives them their
reddish color. Red cells carry oxygen from lungs to all body tissues. Red
cell covering, or membrane, carries A, B, Rh, and other blood factors or anti-
gens .
Rh- compatible . One person is Rh-compatible with another if his red cells cannot
provoke an irninune reaction, due to anti-Rh antibodies, when transfused into
the other. Individuals who are Rh-negative are Rh-compatible with everyone.
Individuals who are Rh-positive are Rh-compatible with other Rh-positive indi-
viduals.
Rh factor. An antigen found on the red cell membrane surface of about 85 per-
cent of humans. It is named after a similar antigen on rhesus monkey red
cells; its chemical composition is unknown. The Rh factor is responsible
for erythroblastosis fetalis and some transfusion reactions.
Rh hemolytic disease. Disease of fetal and early newborn life. It occurs when
red cells from an Rh-positive fetus cross the placenta and provoke an immune
response in an Rh-negative mother. Her anti-Rh antibodies then enter the
fetus, destroying its red cells, and stimulating abnormally high production
of immature cells, or erythroblasts.
Rh immunization. The immunization of an Rh-negative individual to the Rh factor
through deliberate or inadvertent transfusion of Rh-positive blood, or (in
pregnant women) through transplacental passage of fetal Rh-positive red cells
into the maternal circulation.
Rh immunoglobulin. See Rh vaccine.
Rh-incompatible . A person is Rh- incompatible with another if his red cells can
provoke an immune reaction, due to anti-Rh antibodies, when transfused into
the other. A person is Rh-incompatible with another only if he is Rh-positive
and the other is Rh-negative.
Rh-negative. A person whose red cells do not carry the Rh factor is Rh-negative.
Rh-positive. A person whose red cells carry the Rh factor is Rh-positive.
Rh vaccine. Potent anti-Rh antibody, in the form of the 7S fraction of gamma
globulin. The vaccine is administered to a woman unsensitized to the Rh fac-
tor when she delivers a baby in order to prevent her from developing an immu-
nity to the Rh factor that could cause sickness or death in the next Rh-
positive baby she conceives.
RhoGAM. Ortho's registered trade name for Rh vaccine.
Sensitization. See immunization.
Seroconversion . Development of antibodies in response to the administration of
a vaccine.
Serological. Pertaining to the stvady of the antigen-antibody reactions in vitro.
Serum. The clear, liquid part of blood which remains after the red cells and
clotting elements have been removed. The clear liquid which separates from
a clot.
7S. A part of the gamma globulin in which antibodies may exist. The 7S gamma
globulin molecule is relatively small, has two armlike appendages, and will
pass through the placenta from mother to fetus.
Sphingomyelin. A group of phospholipids occurring primarily in nervous tissue
and membranes.
15-137
Spina bifida. A defect involving hernial protrusion of the spinal cord and/or
brain.
Temporal bone. The lateral region of the head above the cheek bone - the temple
region.
Teratogenic. Tending to produce anomalies of formation of the fetus.
Titer. The measure of an antibody's strength. An antibody with a low titer,
1:2, is less potent than one with a higher titer, 1:64, or 1:64,000.
Transfusion reaction. The destruction of incompatible donor blood in a trans-
fusion recipient's bloodstream may quickly produce discomfort, anxiety, dif-
ficulty in breathing, rapid heartbeat, and other distressful symptoms. Kidney
failure and death may follow.
Transplacental passage. Passage through the placental membrane from mother to
fetus or fetus to mother.
Urokinase. A soluble enzyme that promotes the conversion of plasminogen to
plasmin.
Uterus. The female organ in which the young develops from just after conception
to birth.
Vaccine. A substance introduced into the body to prevent disease immunologically.
Vaginal fornix. The recess formed between the vaginal wall and the vaginal part
of the cervix.
Virus (wild and attenuated) . One of a group of minute infectious agents.
Zepherin. A germicidal compound.
15-138
DISCUSSION OF THE PROCEDURE AND COMPLICATIONS OF AMNIOCENTESIS
Technique
The transabdominal approach for purposes of amniocentesis is now the method
of choice based on previous experience with severe complications (e.g. , induced
premature labor, sepsis and severe hemorrhage) associated with the transvaginal
(through the vaginal fornix, either anterior or posterior) and the transcervical
approaches.^' ^^' ■'^' *^' ^°' *^' ■'"^ The actual technique used to enter the amniotic sac
and withdraw fluid has been refined and most clinicians are in agreement on the
steps required to safely obtain a sample of amniotic fluid through the abdominal
wall. .,.;.,,
Preliminary Procedures ,■ ■ '
The bladder should always be voided prior to the operation. In most cases,
this can be done voluntarily without catheterization.
Abdominal Preparation
Strict aseptic procedures must be adhered to throughout the operation to
avoid sepsis. The abdomen should be thoroughly prepared with an antibacterial
solution. Solutions used include alcohol, Zepherine, iodine, and Phisohex. The
abdomen is then draped with sterile towels.
Local Anesthesia ' ;
There are differences of opinion regarding the use of local anesthesia.
Many believe that if the midline is selected carefully or as a general rule, a
local anesthesia is not required."- ^^' ■'''• ''^ Others recommend the injection of
local anesthetics such as lidocaine at the anticipated puncture site.^' i''- 5°- 1°^
There is a strong indication for use of local anesthesia if the patient exhibits
an undue amount of anxiety.
*References are to be found at the end of the section on Amniocentesis.
Location of the Puncture Site
There is no accepted agreement on the puncture site for amniocentesis.
Many have reported that the puncture site should be 2-3 cm above the symphysis
pubis f^-*' ■'^ while others reference from the umbilicus down by as much as 5 cm.^^'*^
The puncture site should, in fact, be determined by previous manual palpation
so that site of entry into the amniotic sac avoids the placenta and is in the
area of fetal small parts.^. 3^. 59, 75, loi The recent introduction of ultrasonography
allows the obstetrician to safely determine the position of the placenta and the
fetus so that puncture of either is minimized. ^2' ^i- ■'^' ■'*• ^3. 54, 85, 119, 124 placentog-
raphy and amniography have also been used for this purpose , 2- ^' i°' ^°- *i but they
are generally not recommended during the second trimester.
Puncturing Procedure
The apparatus used to enter the abdominal cavity has varied from an 18-
gauge needle 1^' ^^' i°i to a 3- to 5-inch long, 21- to 22-gauge spinal needle .^°'52
It has been suggested that a needle with a relatively obtuse angle which is not
well honed will allow the operator to more readily determine the layers of tis-
sue being penetrated. An ACOG Bulletin has recommended that an 18-gauge needle
be inserted through the skin and subcutaneous tissue followed by insertion of a
20-gauge needle through the larger needle into the amniotic cavity.^ This pre-
sumably reduces the possiblity of sepsis.
Obtaining Amniotic Fluid
For diagnostic purposes, amounts of fluid withdrawn range from 5 to 30 or
40 cc. Procedures performed during the second trimester should not withdraw
more than 20 cc. The fluid should be withdrawn very slowly to avoid upsetting
the intrauterine environment and to avoid placental separation. Indications for
repeated procedures are obvious if the sample is grossly contaminated with blood,
or if only blood is obtained when withdrawing the specimen. In addition, hemo-
lytic disease and fetal distress cases may call for several repeat procedures
throughout the pregnancy. It should be noted that plastic syringes are recom-
mended since amniotic fluid cells more readily collect on the walls of glass
syringes.
Postoperative Observation
Many clinicians indicate that fetal heart rate and maternal vital signs
should be monitored from 1-5 hours following the procedure to detect any fetal
distress. S' i^. 34. 35, 108 ip^g mother is generally advised to report any fever,
abdominal pain or cramping including suspected labor, fluid leakage from the
puncture site, or vaginal bleeding after the procedure.
15-140
Timing of the Procedure
The timing of the procedure is based on the type of diagnosis and/or
therapy to be performed. These can be broken down into various categories and
are listed below.
Diagnosis of Genetic Disease
Ideally, the timing for this procedure should be as early as possible in
the second trimester because in certain cases, three to four weeks are required
in order to obtain results from the diagnostic procedures. In such cases, the
parents may elect to induce a therapeutic abortion where a significant genital
defect is diagnosed. Timing is of the essence in this regard since abortions
beyond the 20th week of gestational age are associated with an increase in mater-
nal complications. Unfortunately, there is insufficient amniotic fluid for pur-
poses of amniocentesis prior to at least the 13th week. It has been reported
that amniocentesis to detect genetic defects should be performed at or before
14 weeks;^^ however, others prefer 14 to 16 weeks^- 1^' and still others recommend
16 to 18 weeks. ^®' ■'^^ ^° The consensus seems to be that amniocentesis should be
performed no later than 16 weeks so that if the parents desire, therapeutic abor-
tion can be performed at or prior to the 20th week of gestational age.
Hemolytic Disease :■ c, . '. .
In this case the fetus may show signs of anemia as early as the 32nd week
of gestation in severe cases. However, others feel that the 34th week is most
desirable for optimxjm accuracy in determining fetal anemia under these circum-
stances. It has also been reported that little information is gained after the
36th week,-' although in severe cases, this is not necessarily true.
As far as the mother is concerned, monitoring of Rh antibody titer in her
blood may require amniocentesis as early as 20 to 22 weeks if there is a history
of prenatal death from erythroblastosis. Timing of repeat amniocenteses depends
on the initial results and the previous history. Optical density suggesting
severe disease or history of a previous erythroblastosis prenatal death indicates
repeat amniocentesis at 7 to 10 day intervals. If there is no decrease in fetal
activity or less than a 2-tube rise in the antibody titer, and if the initial
reading was in the mid or low zone, repeat amniocentesis may be deferred for
2 to 3 weeks.
Respiratory Distress Syndrome
This situation is not genetic in origin but occurs as a result of premature
delivery. That is, the fetus's lungs are not sufficiently mature to allow
exchange of oxygen and CO2 in order to survive. The timing for amniocentesis
is based on several maternal factors which would lead to premature delivery.
15-141
These include toxemia, diabetes, incompetent cervix, or a past history of pre-
mature deliveries. Amniocentesis in this situation is usually performed in the
third trimester and can be performed at any time during this period when incipi-
ent premature labor is diagnosed.
Complications
It is important to recognize that complications to both the mother and the
fetus have been reported. However, the incidence of severe complications is
extremely small. It is estimated that over 4,000 midtrimester amniocenteses
have been performed for diagnostic purposes and at least four times that number
during the third trimester for diagnostic and therapeutic purposes. Reports of
isolated severe complications involving death or severe trauma should not cloud
the overall view of the complications of amniocentesis. Complications are mini-
mized by adhering to the procedures described above and by skill of the operator.
The importance of this latter requirement cannot be overemphasized, and an expe-
rienced obstetrician should always perform the procedure.
Maternal Complications
The most frequently reported maternal problems associated with amniocente-
sis are sepsis which include peritonitis and amnionitis (the latter also affects
the fetus) , hemorrhage which can result from perforation of the placenta or umbil-
ical cord (these complications also affect the fetus) , or puncture of a blood
vessel in the myometrium or abdominal tissue. In the case of an Rh-negative
mother and Rh-positive fetus, isoimmunization can result if the fetus, umbilical
cord, or placenta are punctured and fetal blood subsequently enters the maternal
circulation. The complications of induced abortion will not be discussed here,
even though the classic method of withdrawal of amniotic fluid by amniocentesis
is used prior to introduction of abortifacients such as hypertonic glucose or
hypertonic saline. ^^ The risl<s to the mother as a result of the amniocentesis in
conjunction with abortion are identical to those in amniocentesis used for most
other purposes ; however these can be complicated and added to by the abortion
procedure itself.
Table 5 lists the frequency of maternal as well as fetal complications
reported by various investigators. A brief discussion of the major maternal
complications is included below.
Many papers indicate that sepsis to both the mother and the fetus should
not occur with rigid sterile techniques. It has long been accepted that the
transvaginal or transcervical approach has a much higher risk of introducing
sepsis.
The most frequent cause of hemorrhage is perforation of the placenta by
the needle. It has been reported that passage of the needle through the placenta
is not uncommon, with no consequent damage to the mother or the fetus .^® However,
severe problems have been reported due to hemorrhage and are shovm in Table 5.
Another possible problem with hemorrhage is that the amniotic fluid becomes con-
taminated with maternal blood and in the case of sex determination, improper
diagnosis has resulted. Other sources of bleeding involve puncture of the
umbilical cord or a blood vessel in the myometrium which can result in contami-
nation of the amniotic fluid also. Some cases of abdominal bleeding have been
reported but are relatively rare. . , ■ ;: . , •
It has been reported that ultrasonic localization of the placenta virtually
eliminates puncture of the placenta. 12. 3i, 35, 53, as, los, 124 others 2. 9' lO' ^o. si have used
placentography and amniography for the same purpose.
Various clinicians have reported on the induction of abortion or premature
labor, depending on gestational age, following amniocentesis. The reasons for
onset of premature labor leading to abortion or delivery of a premature infant
are not well defined. In many cases, the situation has been confirmed not to
have been caused by the amniocentesis procedure .^^^ ^°' s°
There is a possibility of trauma to other areas of the abdomen such as the
bowel and bladder. This type of complication is extremely rare and when it does
occur, is generally a result of improper procedure.
Abruptio Placenta affects the fetus as much as it does the mother but it
should be considered an extremely infrequent complication. The placenta may
separate as a result of agitation of the intrauterine environment and can gener-
ally be eliminated by not puncturing the placenta and withdrawing the amniotic
fluid at a very slow rate.
Fluid leakage after the procedure has been reported several times. In
most cases, the problem is transient and no sequelae result.^i Rare cases of
amniotic fluid embolism as a result of fluid leakage have been reported .3^ Fluid
leakage may be a result of utilizing a needle with an oversized diameter and this
reinforces the use of a 22-gauge or smaller needle.
Rh isoimmunization is limited to those mothers with Rh negative type blood
and a fetus with Rh positive blood. Rh isoimmunization can occur if the fetus,
lunbilical cord, or placenta is punctured and its blood enters the maternal cir-
culation.i3. 36 Such a situation can affect future pregnancies of the mother.^*
This should be considered a significant potential risk in all Rh-negative mothers
and appropriate means to treat the situation should be available when the mother
is Rh negative.
Failure to obtain amniotic fluid is not a complication per se, but presents
some unique problems which should be discussed. An inability to obtain amniotic
fluid may indicate that the fetus or the placenta has been punctured. It may
also indicate that the needle has not entered the amniotic sac and consequently
the needle should be advanced further. The incidence of not obtaining amniotic
fluid and requirement for repeated procedures is relatively high as shown in
Table 5. Repeated procedures obviously increase the possibility of all other
risks, and this problem is probably the most important which currently exists.
The routine use of ultrasonography in order to locate appropriate puncture sights
where amniotic fluid can be obtained should alleviate most of these situations.
15-143
Fetal Complications. The most common fetal complications associated with
amniocentesis are injury, hemorrhage associated with puncture, errors in diag-
nostic procedure due to twinning or multiple fetuses, death as a result of amni-
onitis, and abortion. Prematurity without death as a result of induced labor
should also be considered a complication. As with the maternal complications,
there are isolated reports of severe trauma and/or death to the fetus attribut-
able to amniocentesis.^^' ^* These cases should be maintained in proper perspec-
tive with relation to the total number of amniocenteses performed. Such cases
can be avoided with proper skill and knowledge of the operator. Table 5 includes
fetal complications and a discussion of those of significance are included below.
Cases of injury to the fetus are most frequent when amniocentesis is per-
formed prior to the 14th week of gestational age or very late in the third tri-
mester. The former is a result of a lack of an adequate amount of fluid, about
50 to 60 cc, as compared with about 350 cc at 17 weeks .^° The problem at or near
term is that the size of the fetus relative to the overall volume of the amniotic
sac is quite large compared with earlier stages of gestational age and thus the
risk of injury at this time is much greater .^^ Even though there is an increased
volume of fluid at 15 to 17 weeks when the procedure is normally performed to
detect genetic defects, there is still a fairly high risk of puncturing the fetus.
However, unless there is severe hemorrhaging, it has been reported that such sus-
pected punctures do not affect the fetus whatsoever and, in particular, do not
induce malformations,20. 35. ^9 as they do in mice or rats.^^' "^' ^^^
Hemorrhage has been reported in a few cases of amniocentesis and is of
particular importance if the mother is Rh negative and the fetus is Rh positive.
In this situation, the fetus may already be anemic and hemorrhage could be fatal.
Ultrasonographic location of the fetus should minimize the risk of perforating
major blood vessels in the fetus since this allows introduction of the needle
into an area where the small parts of the fetus are located. It has been
observed that if a normal fetus is touched with the point of a needle, he will
move away from it.* Many cases of fetal puncture have been attributed to a
hydropic fetus .^"■■'^
Abortion and premature labor, as discussed in the section above on mater-
nal complications, is often not attributable to anniocentesis and, even when it
is, it is difficult to fully describe the reasons. Induction of premature labor
is not a result, in most cases, of injury to the fetus due to the amniocentesis
procedure. It should still, however, be considered a risk when performing the
procedure and is perhaps the most serious risk to the fetus because of lack of
knowledge regarding the causes for induction of labor following amniocentesis.
Errors in diagnosing due to twins or multiple fetuses is a situation which
has been reported on several occasions (e.g., Ref. 27) and all investigators
agree that the routine use of ultrasonography or fetal EGG prior to the procedure
would virtually eliminate this problem.^°' s^- ''^ The problem consists of withdrawing
fluid from the amniotic sac of only one twin in the case of a double sac and using
that fluid for diagnostic purposes.
15-144
Amniography, Ultrasonography, Amnioscopy and Fetoscopy
These three areas are discussed since they have been widely utilized in
conjunction with amniocentesis or in the case of amnioscopy and fetoscopy,
evolved as a result of information gained from amniotic fluid by the procedure
of amniocentesis. '°'
Amniography. Amniography was first performed in 1930 in order to assess
fetal age.^^ Modern use of amniography is invariably restricted to the third
trimester due to associated knowledge of the possibility of induction of fetal
malformation due to exposure to X-radiation earlier in pregnancy. Amniography
can be used to determine fetal age, fetal distress, and fetal death. With the
advent of the introduction of ultrasonography in the middle 1960s, however, the
use of amniography is not generally recommended in conjunction with amniocentesis
due to certain risks associated with it in addition to exposure to X-radiation.
These include the possibility of injection of radioopaque dye into the fetus,
and possible allergic reactions to the dye. Ultrasonography as described below
provides much of the same information with no apparent side effects.
Ultrasonography . Ultrasound has been shown to be safe in obstetrical
diagnosis^' ^^' ^"^ and is suitable for use prior to amniocentesis in the second
and third trimesters to ascertain the gestational age, location of the fetus,
location of the placenta, and the occurrence of twinning or multiple fetuses.
The value of having this information has been discussed previously and its
importance cannot be overemphasized. The use of ultrasonography prior to amnio-
centesis is fast becoming a routine procedure in order to avoid certain compli-
cations. • . . -
Amnioscopy and Fetoscopy. Transcervical amnioscopy and fetoscopy were
introduced due to an increased interest in obtaining knowledge of the intrauter-
ine environment and the fetus during pregnancy. This valuable diagnostic tool
has been refined to the point where endoscopes can be introduced through the
abdominal wall (now generally referred to as fetoscopy) . The procedure is now
relatively safe, and it can provide information regarding fetal malformations
and other anomalies in utero , such as fetal distress, and location and condition
of the placenta.
15-145
^
o
£
£
5
£
1
1
§
3
o.
i
E
&
1
g
J
1
c"
1
1
1
1
1
<
ll
1
<
s
0 „ ,2
DnN
aps.
ntagi
licat
..,
o
o
^Z 5 1
o
S!
°
°
o
°
o
o
'-
o
5
£!
o
|=£5
°
S s
c
c
c
o
E ^
z
z
Z
2
z
2
E
E
z
^
2
3
u
c
3
D.
1
I
1
1
1
1
1
I
1
1
.S
u
o-S
"o
« >
3
u
y
u
u
CT 5
u
« £
i 1
!»
1
1
£
i
1
si
>
i
1
1
.1 o
^
1 1
£ <
1 1 1
I|
>
1
i
<
1
1
<
1 i
f s
s 1
If
11
1 1
2 S
§ c
II
1 -
►- " 2
- E c
■? 8 i
o
o
|l!
o
o
o
ro
o 3
a
^
o
o
«
S
s
o
a.
„
^
S
§
O
"
(rt
1
1
1
s
1
1
£
1
ro
5
Q
^
<3
CD
£
1
!
g
1
°
s
1
?
m
^
=
«
?
(U
£
^
*z
J£
t;
Q
1
^
s
1
1
1
1
1
1
1
i3
1
3
i
R
s
i
s
s
i
i
i
S
s
s
>
2
2
2
2
2
2
-
-
15-147
c
I
chorioamnio-
duced. Also
rn 20.5 per-
24.5 percent
ncture with-
i
1
•2 1
If
1
I
1
o
a
£
E
3
c
1
liilii
1
£
a
i
f 1
1
1
5
1
1
s
1
1
0
1
1 || 8 f 1
%
1
1 s
1 ^
1 s
i i
5
i
■o c
11
1
£
n
"1^1^=
° £ 1
1 i
N c -S S S o
"-
"
u. a
"
S
a.
£
latl
in
o
fN
^
«
CH
S O o o
°
^
S
°
(M
°
°
°
o
'
o
o
°
<3 °-i^
°
^ c
o .9
5
5 S
c
E
E ^
z
z
z
Z
z
z
M
°
>■
.c
a
a
□1
«
2
£
1
1
1
1
1
i
1
1
1
1
1
1
1
a
u
i
o .2
.y
u
«
,y
ti S
j: tr
c c
>
>
>
>
>
>
> §
t s
^
>
.2 8
8 1
11
o
O
o
"5
i
1
E
1
E
c =
i
2
i i
1
E
1 1
f s
1^
- i
ll
i 1 1
•= s
2 S
|i
1 °
2 S
£ S
© .2
at .2
cS 8
u. -a
U. TJ
u. -o
U- TJ
<^ a a
u. a
u. -o
U. -D
«
'" c ^
1 ^ =
g
1
1
1
1
1
1
1
1
1
1
1
1
1 °- 5
a ~
&
o,
o
o
5
IS
<■>
CO
01
D
o
S
g
in
*"
S
c
.£
1
1
1
£
^
s
N
i
1
is
s:
O
IT
_■
X
£
«
3
<
1
E
1
c
1
i
i
>
1
>
1
1
s
2
1
1
1
1
c
3
i!
1
1
i
3
&
5
i
1
1
§
§
^
^
IN
CN
„
IM
N
„
8
>-
i
i
i
i
i
8
S
m
m
s
^
•"
""
■^
""
"
"
*"
*"
""
""
"
"
15-148
if
8 , s«
WU.
S g g li! £
fl
ned in 4
ants del
ransfus
bloody
nts with
>
1
obta
cinf
nge
ernal
patie
hout
1
? tf i " 1
91
£ I § &
3 S 2
ll
if
I 5 t
ll!
31 i
?l
I t -
o I 8 a o g
1 1 Ills f2 !f?H-2 li I
H _
1^1
I I I
I I J ^
£ J I s
15-149
= ,
1
? 1
c
•-si
n
» €
.2
2 J
8
5 r •o
1
(N
>■ a
«
■O ra
Q.
C £ O
s
S
g
o r ^
Q
lis
E
■D
£
f 1
1
ei
1
E
3
III
III
'c
.2
E o
1
1
5
i
2
1
o
1
i^ S 1
11
u Z
§?l
E
<
1
<
s
g
z ^- oi '5
c a £ 8
o a c =
Based 1
ofT
Perce
Comp
^
°
°
°
^
°
0)
°
""
°
o
o
°
•*- c
0 .2
1 .1
^
s
c
c
c
in
i
?
o
^1
o
0
i
z
Z
Z
z
E
z
z
z
s
1
«
c
E
S
■g 6
1
c "^
•^
1
n 3
^CM
«
■?■?
is
^(3
(3 i
's'k.
ii
u
- s
y
u
„
„
8
u
y
„
2
u
c E
.2 S
i
f
1
>
1
11
|,E .
fill
1
>
i
f
11
E
1
8 i
II
- ^
ii
ii
II
1 1
o S I
* 1 1
1 £ i i
- i
s i
- i
1 i
11
ii
u. -a
u. -6
li- TJ
u. ?
D 3 £
u. -5
U. TJ
U. -D
a i
£ 5
»
1= - ^
III
1
1
1
S
1
§
1
S
1
5
1
1
1
§^5
""
<ii ~
«
CN
15
V
o
o
§
in
,
S
5
in
§
?
^
<r
a
1
s
1
1
1
^
1
s
1
1
?
1
8
1
£
^
c
i
f
S
o
1
i
!
1
1
•Q
s
<^
■?
<
«
1
ro
?
s
1
■g
1
1
1
1
1
1
o
1
1
5
6
1
■p
if
>
i
g
i
s
S
i
1
i
i
s
S
i
i
*"
"
"
"
"
-
^
-
^
^
15-150
I
%
>.
>
1.C
S £
11!
ll §
1 o f
iis
lis
i S 8
iT E <N
?i^
<u -^ —
8
1
1
i 1
1
1
- 1
1 1
1
1
■s
1
i
1
1
1
1
li
1
s
5 1
1^.
III
c E .
Ill
i 1 °
1 i 1 a
s g a s
■S 5 i 1
5 ^ s f
- 1 c ^.
ifll
S S t
1 s
z 3
li
I
is
Is
!H!
|l||
»
= as|
of T
omp
o
g
o
u>
2
°
o
o
S °- if
°
•,- c
1 5
1
c
^
c
(^
c
^
CO
5
1-
li
z
2
Z
-
Z
S
i i
"
"
_
£
o
t
3
E
a
°
.2 -o
S =
3
1
a »
S
Q.
- 2
O
°
§tE
a
5
w
1 §
z a 2
2 § o
£ S ■£
1
.2
E
- i
ra £
S
u) £
o ■£ £
«
c c
£
-g
1
1
1
1
1
ESS
° 1
1
11
111
f
E
<
1
<
E
<
&
S " K
1 S §
III
ll
^1
a _
1^ ?l
lii
'
'
'
'
,
§" 6
^ -
1
o
,
sn
s
o
S
CO
i
<f
g
*"
"
§
j;
^
1
1
S.
T"
1
£
a
0
£
1
C
■D
C
<
5
E
E
•J
>
i
c
3
f
S
1
1
1
^
1
1
d
1
1
1
s
s
i
~%
i
s
i
s
s
S
£
s
i
''
"
"
"
"
-
"
^
"
^
""
*"
15-151
^ i k a
=> K ^ ?
¥ s a B
Jill
s -, »
I i f f H I
1 ' I E i S i
1 II- !||l:-l
• 111 ii-2-l
I I I I I I
2 1 ! 1 1 1
■g » E s E g
3 t t = t
^ 8<3 i
E 1 E e
iMi
I el?
sill
I ii » S
Tit 8 I
•6
M
S o
s I
S > I
II
6 -,^
•s IS
■D O C
I II
C ra C
<S & I
I*
It
1
I 5
15-152
1
1
<s
g
1
1
s
1
,1 1 ? 1 t
JjlJJ
&
1
i
1
1
1
c
s
>
ll
I f
1
1
II
a
s
s
S £ c '^ g
"
1
r-
m ~
is
E
s
^ «
!
f I'S i 1 1
1
1
c
S
1
° ^ %
ll
ll
If
lii ill
ll
§
§
1
III
i ^
11
•5 ■£ !! " c 1
£ 1 5 i i -s
— ^
1
1
^
ill
2 ja
.
2 « ™ S
S
2
E III
q
^
^
£
g
^
Based c
Parcel
f CompI
O
O
O
E
E
E
E
S
"
"
1
a)
0 1
|l
1
i
i
5.1
«
.a o
1-
C
o
fc S
<D
•-
g^
E
E
3
s
f^
a
1
£
E
E
^ E
1 1
z 2
1
1
8
1
S
<T
1
-D
U,
1
1
3
3 3
1
1
1
5 >
1
1
1
1
31
> —
1
1
.f "
^
S J
o 1
t§
*? °-
~
§ §
CN 3
|2
is
t 3
~ 1
G
i
S
s
^ ^ -?
Is
1
1
1
s
o g
1
"ffl
■«
"o ^
c 2
o g
oJ J2
^ o
5
o
if
■a
1
s
•D
1
1 i
1 5
E 1
1 1
li
11
|5
llf
5 « g
i 1 -g
§1,
< 5 €
1
s
E
if
a ^
111
o
o
o
o
'
S
'
1
1
1
1
1
II
i
5 ~
—
a
CD
<D
o
K
1
^
CN
lO
s
CO
'"
s
^
.1
1
1
1
r)
1
1
1
"
5
8
p
^
£
.
1
1
-3
3
<
S
g
1
=
1
1
t
s
O)
i
1
£
O
s
1
H
1
1
5
o
^
o
^
^
^
(N
CN
„
^
^
T
n
■*
1
£
m
s
m
s
S)
S)
Si
05
Si
a)
S)
>
^
-
^
-
-
^
^
'"
-
"
"
15-153
CRITIQUE OF BATTELLE REPORT
Robert E. Cooke, M.D. ,
Commissioner
CRITIQUE OF BATTELLE REPORT
Robert E. Cooke, M.D. ,
Commissioner
One of the most critical questions put to the National Commission on the
Protection of Human Subjects is that of the necessity for research utilizing
the living human fetus in utero or ex utero when the research is not for the
benefit of that particular fetus.
Testimony has been given and denied as to the necessity for such research
in solving important practical problems affecting significant numbers of persons
in the near future.
The integrity of the Commission in the minds of groups of different views —
all heavily emotionally involved — laity, clergy, scientists — will depend upon
the objectivity and impartiality of the answers provided to the issue posed.
The only true objective approach beyond question, since scientists make
this analysis, is to collect information and analyze past research accomplish-
ments with the intention of disproving, not proving the hypothesis that research
utilizing the living human fetus nonbenef icially is necessary.
In the neurosciences , for example, the presumption (without laws or bans)
has existed that invasive nonbenef icial research on the human brain is out of
the question. With that presumption great progress has been made in understanding
a very complex organ or collection of organs by highly creative animal research,
by study of human pathological material synthesized with clinical and therapeutic
research.
An analysis of the understanding of human brain function could either
emphasize superficially living human research or could show by very detailed
and painstaking analysis the enormous contribution made by animal studies — the
latter being closer to the facts.
In general in relation to the problem of nonbenef icial research on the
living human fetus, the Battelle Report in part because of time constraints,
but probably also because of orientation, does not challenge sufficiently the
stated hypothesis.
The emphasis in the report is placed:
1. On what some would consider relatively trivial contributions —
sharpness of needle, etc., in amniocentesis.
2. On contributions from human therapeutic research — in the
premature infant in hyaline membrane disease.
15-155
3. On living tissues from the dead fetus — rubella.
4. On fluid (and cells therein) from around the fetus or fetal
membranes, placenta, placental vessels, etc., in prenatal
genetic disease detection.
5. On fetal therapeutic research as in hydrops fetalis associated
with Rh disease rather than on nonbenef icial research on the
living human fetus in utero or ex utero.
The report is written as though human research is in question and substan-
tial credibility of the report as regards fetal research is thereby lost.
In fact most of the research cited was done before any significant number
of legalized abortions were being carried out and practically none of the work
in Rh disease or hyaline membrane disease used abortuses. Abortuses were used
in rubella and amniocentesis but the necessity for their use is addressed below.
The biased orientation appears throughout. In the introduction, page 15-5,
the statement is made that "amniocentesis is central to research leading to an
understanding, characterization, and detection of the disease (congenital rubella
syndrome)." That statement is utterly false. Minimal information has or is being
gained in rubella from amniocentesis. Living human fetal research or nonbenef icial
nature played essentially no role in Rh disease. Transfusion therapy was for the
benefit of that fetus. Rh vaccine required maternal blood samples — not fetal
research. The introduction, page 15-5, further implies that without amniocentesis
and/or fetal research there would be "no basis for successful research toward pre-
vention or cure" in RDS or hemolytic disease. These statements are gross exag-
gerations as well. Animal research or research on lungs of dead prematures shed
enormous light on RDS and exchange transfusion in living newborns was the giant
step in Rh disease.
Such a bias vitiates the claim (page 15-5) that "dependence must be placed
on the judgement of qualified persons that proceeding to research involving living
human fetuses is justified on the basis of research/benefit considerations."
In RDS — the major fetal contribution has been the L/S ratio as an indicator
of lung maturity. Now its use is strictly therapeutic. The earlier collection
of amniotic fluid to establish normative data could have been collected oppor-
tunistically from amniotic fluid at caesarean section and correlated with other
indicators of maturity and survival. However, even the amniotic fluid studies
cited as fetal research were noninvasive to the fetus per se and probably accep-
table to most religious groups. The study of lung inflation curves, of surfac-
tant levels, of steroid induction of biochemical maturation of the lung did not
require living human fetuses.
The study of transplacental movement of steroid near term to induce lung
maturation did not require abortuses and elective caesarean section would suf-
fice.
15-156
In the development of the rubella vaccine, the report indicates that use
of animals to study transplacental passage of the vaccine virus was misleading.
The initial studies utilized only six rhesus monkeys. No other animals were
used. A positive take in any one should have been enough to raise serious
doubts as to its use in pregnant women.
Likewise, the use of pregnant women — intentionally vaccinated prior to
abortion is said to have been essential to discover the threat to future fetuses.
However, despite this report accidental vaccine infection of the fetus was
reported shortly thereafter thereby vitiating the original intent to avoid
accidental infection.
On page 15-14 the sensitivity of the reporters must be further questioned.
The report suggests that women who are to be aborted and who are presumably
vaccinated might be challenged by wild type virus intentionally to show fetal
protection by the previous immunization procedures. No concern is expressed
regarding possible illness in the mothers from wild type rubella — a not
totally benign illness in adult females.
In rubella, then, epidemiologic investigations clearly established and
characterized the congenital rubella syndrome. Maternal serologic studies
and clinical follow-up established the frequency of damage. The danger of the
vaccine to the human fetus was learned accidentally despite in utero fetal
research. Retrospectively in utero fetal research might have been justified
before any use of the vaccine so that accidental infection would have been
avoided, however, in fact such research did not prevent later accidental
infection.
In the discussion of amniocentesis, the bias of the report continues. In
the benefit to cost calculation, for example, the average age of Down's Syndrome
used in the calculation is 50 years. Penrose, in his book, gives the correct
average longevity of DS as 16 years. The report, therefore, increases benefit
by a factor of 3. Present longevity may be closer to 20 years.
In discussions of the technique of amniocentesis most of the "advances"
are minor technical ones, "the type and degree of sharpness of the needle,"
not substantive research and such information could have been gained as part
of therapeutic research for Rh disease, etc., or probably from animal studies.
The use of ultrasound could be developed in animals readily.
The assertion that the techniques could not have been developed in animals
is unreasonable. Certainly the Blalock-Taussig procedure for cyanotic heart
disease is conceptually and technically far more complex than amniocentesis.
Yet, all details of the surgery were worked out not in humans but in dogs that
do not even have tetralogy of Fallot.
In the discussion of amniocentesis, detection of defects through tissue
culture utilized living cells shed into fluid — not the living fetus. Normative
values for enzymes were obtained in significant numbers from the use of amnio-
tic fluid obtained at the time of abortion not from the living fetus.
In the discussion of Rh disease — "three major phases are cited as requiring
human fetal research."
1. Fetal cells in the maternal circulation. Maternal sensitization
and antibody coating were already well known; hence "fetal research"
was not fetal research. It required small samples of maternal
blood.
2. Maternal anti-Rh antibodies found on fetal (newborn more exactly)
cells by Coomb's test. Fetal research not required.
3. The postnatal CNS effects of bilirubin and the lack of damage to
the fetus was known without live fetal research and the prevention
of hernicterus by exchange transfusion which was an enormous
achievement (Diamond and Allen) required no fetal research.
Likewise, Phogam development to prevent Rh sensitization at delivery or
abortion did not require studying of the living fetus.
Indeed, the three areas cited, pages 15-62 and 15-63, were very minor in
the picture of the solving of the Rh story.
The same effort to justify fetal research comes through on page 15-63.
The large number of stillborns referred to from E. F. with hydrops implies that
the major advances in Rh disease were fetal. That is incorrect just as is the
summary statement, page 15-63, "It was through this sequence of critical advances
in human fetal research that the Rh vaccine was conceived and the threat of Rh
disease brought under control."
On page 15-64 a list of so-called critical questions is presented to sug-
gest that the ban on fetal research would have affected most of the discoveries.
The answer to all are "yes" not "no" (except 3 - "the same") without beneficial
research on the living human fetus in utero or ex utero.
The statement that a "ban on fetal research would not have allowed this
understanding of the mechanism of Rh disease in hiomans to evolve over the short
span of 15 years" is simply not true. The understanding came without the research
which is now banned.
The RDS story is similar to the other areas cited. Fetal research was
necessary — namely, research on dead premature infant lungs, fetal fluid obtained
by amniocentesis near term to guide therapy of that infant and fetal research
on animals. Thus, a ban on research on the living human fetus obtained by
abortion would not have prevented the present advances. Therapeutic efforts
aimed at the near-term or premature infant with hyaline membrane disease are
not prevented by any such ban.
In conclusion, the Battelle Report has erred as many scientists have done
in trying to justify the importance of human research by failing to challenge
15-158
objectively the need for nonbenef icial research on the living human fetus in
utero or ex utero. As a scientist, I feel the evidence must be exhaustively
searched to show absolutely unequivocally, not subject to dispute by anyone,
that some vital link in the chain that led to the solution of a problem that
all men of good will would agree was important required the nonbenef icial non-
therapeutic use of a living human fetus in utero or ex utero.
The Battelle Report has not done so in my opinion and unfortunately has
been presented unchallenged in the press as authoritative.
The revised final report unfortunately can not dispel the earlier impres-
sions. The distinction between therapeutic and nontherapeutic is helpful.
The discussion of animal models is more objective. The basic problem, however,
still exists.
RESPONSE TO THE COOKE CRITIQUE
RESPONSE TO THE COOKE CRITIQUE
From reading the critique, it appears that the primary difficulty arose
from differences in the definition of "fetal research." Our working definition,
as stated in the Introduction and the Overall Conclusions, was "any experimenta-
tion on either the pregnant woman or the fetus in which either drugs or surgical
procedures are involved." Thus we included numerous examples which Dr. Cooke,
using a more restricted definition, does not consider fetal research.
For clarity, his comments are discussed by individual cases.
Congenital Rubella Syndrome
Our report agrees with him that fetal research played no part in estab-
lishing the association of CRS with rubella or in the development of the vaccine.
As to the fetal research involved in studies of vaccine transmission transplacen-
tally to the fetus, we agree that the first study did involve some women who were
unknowingly pregnant. It and subsequent studies did delineate the risk of the
vaccine to fetuses and establish the proper time for vaccination. While only six
rhesus monkeys were used in the transplacental study that led to the above-
mentioned fetal research (vaccination of pregnant women before planned abortions) ,
we agree with a number of investigators that the fetal research was necessary.
To have waited for the vaccination of pregnant women to show the vaccine passage
across the placenta would have meant either the birth of infected infants or
unwanted abortions. As to the intentional challenge by wild virus to vaccinated
women, we did not "suggest" it. We merely pointed out that such an experiment
would represent the ultimate test of the effectiveness of the vaccine.
Amniocentesis . . _ .,
Here especially the problem of the definition of fetal research appears.
By our given definition, withdrawal of amniotic fluid to determine the status
of a fetus is fetal research until the diagnosis involved is regarded as an
established procedure. Thus, the studies involving amniocentesis in Rh-immune
disease, respiratory distress syndrome, and the determination of genetic defects,
at the time they were done, qualified as fetal research. As to the adequacy of
animal models for the procedure of amniocentesis, there is obviously a differ-
ence of opinion. We gave our assessment of the evidence. The Yale report
reached the same conclusion.
15-161
Dr. Cooke also criticized our use of 50 years as the life expectancy of
children with Down's syndrome. Our reference for this figure is Milunsky in
The Prenatal Diagnosis of Hereditary Disorders , 1973, Charles C. Thomas pub-
lisher. A reproduction of the relevant pages is attached.
Rh Vaccine
As to the areas given on pages 15-62 and 15-63, we stand on our statement
that their definition was necessary to the understanding of the mechanism of
erythroblastosis. Under the given definition of fetal research, study of the
pregnant woman's blood qualifies as fetal research. Mengert in 1955 used amni-
otic fluid, thereby qualifying the study as fetal research. The work of Diamond
and Allen was described in the report as not involving fetal research. It should
be noted however, that the postnatal transfusions perfected by Diamond and Allen
of course did nothing for the fetuses dying in utero. The intrauterine trans-
fusion procedure was a result of fetal research.
As regards Dr. Cooke's comments on the questions on page 15-64, unfortunately
we did not give explicit answers in a 1 , 2, 3, . . . series. The pages following,
however, do show that not all research was fetal and that some was fetal by our
definition, though not by Dr. Cooke's.
Respiratory Distress Syndrome
Here again, the definition of fetal research has caused problems. We con-
sider the studies on L/S ratio via amniocentesis to be fetal research; Dr. Cooke
does not. Antenatal therapeutic studies, as with corticosteroids, are fetal
research by the definition used; Dr. Cooke does not consider these as fetal
research.
To summarize, the conclusions we reached in our study were based on a given
definition of research on living fetuses. Using Dr. Cooke's definition, many,
perhaps even most, research studies described in the report would not have been
classified as fetal research. Had we used his definition, our conclusions would
have been drastically altered.
R. I. Leininger
Battelle's Columbus Laboratories
April 21, 1975
15-162
From A. Milunsky, The Prenatal Diagnosis of Hereditary Disorders
(Springfield, 111.: Charles C. Thomas, 1973, pp. 166 to 167)
If the risk of bearing a chromosomally abnormal child in the thirty-five
to thirty-nine year age range is about 1:60 (see Chapter 11), then an estimated
4,667 defective offspring will be born in this group. Similarly, with a risk of
about 1:40, about 3,000 defective offspring will be born in the group of mothers
aged forty or over. Together this represents a total of 7,667 seriously defec-
tive offspring born each year to 400,000 mothers over thirty-five years of age
in the U.S.A.
If amniocentesis and prenatal genetic studies were routinely provided for
women over thirty-five years of age, then the cost of 400,000 cases would be
about $50 million. To this would be added the cost of therapeutic abortion by
the generally preferred technique of hypertonic saline induction or the 2 to
3 percent of cases which require termination of pregnancy by hysterotomy.
This computed cost would be about $3,250,400 for terminating the 7,667
pregnancies with defective fetuses, assuming all couples requested such action
and that the cost of saline induction does not exceed $400 (known range for
outpatient to inpatient saline induction is $100 to 400) and hysterotomy, $800.
Hence, the cost of prenatal diagnosis and therapeutic abortion when necessary
for 400,000 mothers over thirty-five years of age would be about $63 million.
The cost of care for the 7,667 defective offspring that would otherwise
be born is not easily assessed. For the majority of these patients the defects
would be serious enough to result in institutionalization sooner or later.
Current figures at the Walter E. Fernald State School for Retarded Children in
Waltham, Massachusetts, indicate that the average cost of residential care for
outpatient is $6,100 per year. Assuming an average life expectancy of fifty
years, it would cost an estimated $305,000 for the life-time care of one patient.
For 7,557 patients the conservative figure for care in one year would therefore
reach the astronomical figure of $460 million, and for the projected life-time
care $2,338,435,000. Hence, the birth of 7,667 chromosomally defective offspring
in one year could ultimately cost society in excess of 2 billion dollars — about
thirty-two times the cost of prevention through prenatal diagnosis and therapeu-
tic abortion.
Each year with the birth of a similar number of chromosome-defective
offspring (mainly with mongolism) a future committment in excess of 2 billion
dollars is created. In twenty years of present costs (which of course will not
apply) the commitment will have grown to about 40 billion dollars , a figure not
very dissimilar to the recent calculations of Swanson (853) .
These estimates have been made with the full realization that the tendency
to institutionalize early or at all is said to be changing. (Admission ages to
the VJalter E. Fernald State School has not changed significantly over the past
decade, with one-fourth of the patients admitted between zero to five years,
five-twelfths between six to fifteen years and one-third over fifteen years of
age.) The significant death rate in the first five years of age for children
with Down's syndrome is knov/n (155) but is rapidly decreasing. The life expec-
tancy for increasing numbers of patients . . .
16
THE STABILITY OF THE DECISION
TO SEEK INDUCED ABORTION
Michael B. Bracken, M.P.H., Ph.D.
1ICHAEL B. BRACKEN, M.P.H., Ph.D.
Dr. Bracken is presently Research Associate in
Epidemiology, Yale University Medical School.
PD 304190-5(11)
The Stability of the Decision
to Seek Induced Abortion
INTRODUCTION
This paper focuses on the stability of the decision to seek an induced
abortion. Three areas are considered: (a) the available literature has been
reviewed, and some previously unpublished data are presented, in a manner which
sheds a little light on the frequency with which women change their mind about
seeking induced abortion; (b) evidence suggesting possible characteristics of
women who might be at higher risk of changing their mind about deciding to
abort is reviewed; and (c) some psychological and situational factors which
might contribute to a change in the decision to abort are examined.
In addition to attempting to collect and integrate currently available
material in a manner which contributes to our knowledge of the problem of
decision-making stability prior to seeking induced abortion, the reviewer has
attempted to limit his observations to issues of particular pertinence to the
National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research. The review, therefore, has two further restrictions.
First, the literature published before 1970 has not been generally con-
sidered although in at least one case ^ the data presented were collected prior
to that time. While there is some evidence from other countries to suggest
that restrictive abortion laws have less than total impact in preventing women
from seeking abortion " studies from Britain and the United States show a con-
siderable increase in the number of women obtaining abortions following liber-
alization of abortion laws. In Britain, since the 1967 Abortion Act, the rate
of abortion per 1000 resident women ages 15 to 44 has risen from 3.5 in 1968
to 10.0 in 1971.6 jj^ ^^le United States approximately 200,000 legal abortions
were performed in 1970, 745,400 in 1973 (a rate of 16.5 abortions per 1000
women aged 15 to 44) and it has been projected that in 1974, 892,000 legal
abortions were performed.^ These data also show that the United States Supreme
Court Decision in 1973,* which liberalized abortion laws, did not have a partic-
ularly marked effect on what has been a steady annual increase in the rate of
abortion, in the United States, since the late 1960s when several states enacted
less restrictive abortion codes.
The second restriction in the current review is that only one aspect of
the stability of the abortion decision — the change from a decision to abort to
one in favor of delivery — has been considered. As we shall see below, decision
making during unwanted pregnancy may include periods in which a woman continu-
ally revises and re-revises the options open to her. While a decision to deliver
may later be changed to a decision to abort ^'^^ (or regret that abortion can no
longer, for medical reasons, be performed) , this change in decision is not con-
sidered further in this paper.
THE RATE AT WHICH WOMEN CHANGE THEIR MIND ABOUT ABORTION
In reviewing the available information on the rate at which women change
their mind about abortion we will consider three aspects of the source of evi-
dence: (1) the period in the individual's own decision making when the change
in decision was ascertained, (2) the location — clinic, hospital, county and
socio-legal conditions in effect when the data were collected, and (3) the
nature of the statistic itself — including factors influencing the numerator and
denominator which may effect the computed rate.
The Period of Decision Making During Which Indecision May Occur
All women who experience pregnancy may consider the possibility of abor-
tion and, therefore, are at risk of changing their decision from abortion to
delivery. Nonetheless, it is clear that many women who become pregnant unequiv-
ocally wish for the pregnancy to lead to delivery and for them abortion is not
a serious option. Other women, however, variously described as having an
unwanted or unplanned pregnancy,^ give abortion considerable consideration. It
is convenient to examine the stability of the decision process, in these women,
for two periods: (a) the time between suspecting pregnancy and making an
appointment at an abortion facility, and (b) the time between visiting an abor-
tion facility and actually having the abortion. While such a dichotomy helps
us to examine the decision process on an empirical level, however, it does not
necessarily conform with the psychological reality of the decision process
itself.
Evidence from studies of the first period of decision making may be most
useful in predicting the characteristics of women who will change their decision
to abort after reaching the clinic, and in predicting the psychological and
situational correlates of such a change. Decisions which occur after the abor-
tion client has made personal contact with an abortion facility are of acute
interest to the Commission since this is the time when a voman is most likely
to be asked to participate in medical studies.
The Time Between Suspicion of Pregnancy and Personal Contact at the Clinic
In a study carried out at Yale-New Haven Hospital and also at a private
New York Clinic women who aborted were asked to retrospectively report how
frequently they changed their mind about the decision to abort. Approximately
one third of the respondents had changed their minds about the decision to
abort at least once (Table 1) ."
16-2
Distribution of Variable-Indecision About Abortion
and Association with Gestation Group*
New York
New
Haven
Times changed
mind about
Black
White
abortion
No. Percent
No. Percent
No. Percent
Never
197 62.3
74 71.8
126 72.0
Once or twice
83 26.3
17 16.5
35 20.0
Many times/all
36 11.4
12 11.7
14 8.0
the time
Gestation
Percent changed
Percent changed
Percent changed
group
mind about
mind about
mind about
(weeks)
abortion
No.
abortion
No.
abortion
No.
< 9
27.5
80
20.0
10
25.8
31
9-12
32.5
83
42.8
28
23.9
71
13-18
48.2
85
21.3
47
32.2
59
> 18
40.0
75
27.9
18
35.7
14
**p < 0.01
Y = .19**
Y = .15
Y = .14
•Source: Table is reprinted from Bracken.'^
A less direct way of considering the frequency with which women may change
their mind about the abortion is to examine the difficulty in making the decision.
Women aborting at the State University Hospital in Syracuse, New York, between
July 1970 and June 1971, were asked about their decision to abort and reported
that it was: not difficult 55 percent; mildly difficult 20 percent; considerably
difficult 24 percent. Similar results were found in the New Haven and New York
Study ^^ in which abortion clients were asked to rank, on a 7-point scale, whether
their decision had been extremely easy (scored 1) or extremely difficult (scored
7) . The mean scores for women aborting in both New Haven and New York were 3.3
indicating that almost half the women had experienced some difficulty in making
their decision. In another New York study at Park East Hospital, carried out
between December 1971 and April 1972, one-fourth of the women aborting found the
deci.sion "difficult to make."-'''
Another way of obtaining some estimate of the risk for a change in the
decision to abort is to measure the degree of conflict during the decision
16-3
process. When this was done in the New Haven and New York studies mean levels
of conflict of 2.5 were found (measured on a 7-point scale where 1 = low and
7 = high conflict) ."•^''
Yet another way of estimating the level of indecision during this period
is to determine the number of women who make appointments at abortion facilities
but fail to keep them. The results of a small, ad hoc survey designed to col-
lect data on the frequency of missed appointments are shown in Table 2.
Inspection of Table 2 suggests that roughly 10 percent of appointments
made for first trimester abortion are not kept. It would be wrong, however, to
interpret this figure as anything other than a maximum estimate for women who
have decided not to abort. It was mentioned at all clinics surveyed that an
appointment might be missed because a woman had elected to abort at another
clinic, or that the appointment was inconvenient and might be rescheduled (much,
but probably not all, of duplicate scheduling was avoided in computing clinic
statistics) , or that the client found she was not pregnant, or had spontaneously
aborted.
Table 2. Proportion of Women Failing to Keep Clinic Appointments
for First Trimester Abortions
Number of
Number of
Percent
Women Making
Women Missing
Missed
Source
Year
Appointments
Appo
intments
Appointments
Eastern Women ' s
Feb 1 to
11,765
1,360
11.6
Center, New York^°
Aug 1, 1972
Eastern Women's
1973
9,830
1,493
15.2
Center, New York^o
Nathanson^^
Jul 1970
Aug 1971
to
29,696
1,848
6.2
Preterm, Boston^'
Dec 1974
Feb 1975
to
2,758
237
8.5
Erie Medical
1973
7,061
646
9.1
Center, Buffalo,
New York^s
1974
5,041
369
7.3
Decision Changes Following Personal Contact with Abortion Facility
The essential information collected for this section is presented in
Table 3. In order to determine the rate at which women change their decision
to abort after making personal contact with the abortion clinic, an attempt has
been made to standardize the rate as follows:
■ Number of women reported
Rate of women deciding to deliver _ deciding to deliver
after visiting abortion clinic Total number of women visiting clinic
for abortion in same time period
The reported rates range from a low of 0.05 percent to 9.7 percent, a 162-
fold difference! In order to weight the evidence in Table 3 we will review the
sources of data in more detail in the following two sections.
The Type of Abortion Facility from Which Rates were Obtained
The effect of different types of abortion facility on the rate at which
women change their decision to abort is highlighted by contrasting the two
facilities showing the extreme differences in rate. Grady Memorial Hospital,
at the time of the study ,'8 was a 1,100 bed hospital serving medically indigent
people from Atlanta. In 1970, in order for a woman to obtain an abortion, three
licensed physicians and two out of three members of a hospital committee had to
agree that an abortion was necessary. This system continued in the hospital
even after a Georgia Federal District Court had ruled, in July of 1970, that
established specific indications for abortion were unconstitutional. During
1970, 341 women applied for abortion of whom 139 were found to be "ineligible"
or withdrew before they could be presented to the abortion committee, 43 women
who were presented were refused abortion and 134 women were aborted. The median
time for the abortion work-up was reported to be 15 days. In this, rather for-
midable, institutional and psychosocial environment, 31 women were reported to
have changed their decision to abort (Table 3) .
Eastern Women's Center ^° is typical of many large clinics specializing in
abortion and reproductive health found in the United States at the present time
and a description of the routines for obtaining abortion at other clinics '^'^^
could equally apply there. Most appointments are made by telephone after the
abortion client has, in many cases, already been counseled by a family planning
or other agency counselor. When the abortion patient visits the clinic she is
examined, counseled and aborted on the same day. Counseling at free standing
abortion clinics provides emotional support prior to, sometimes during, and
often following the abortion. ^■'"^^ In 1973, at Eastern Women's Center, 553 women
were denied abortion because of advanced gestation, 3 women were found on medical
examination to have medical contraindications, 7 women decided not to abort and
7,770 women had an abortion.
Table 3. Description of Studies Providing Rates for Women Who Decide
Not to Abort After Personal Contact With Abortion Facility
Source
Year of Data
Collection
Stages in Referral for Abortion
Rates*
Patients Referred
From
Patients Referred
To
Time When Decision
to Abort was Changed
Newton etal.^*
1972
General practitioners
and family planning
clinics
Abortion CounseUng
Clinic, King's College
Hospital, London
After fust
contact with
Abortion Clinic**
26/1,173
(2.2%)
Bracken and
Swigai^'
1970-1971
Family planning
cUnics. referral
agencies and
physicians
Yale-New Haven
Hospital. Connecticut
After first
contact with
Abortion CUrtic**
31/474
(6.6%)
Bracken"
1972-1973
Initial visit at
Yale-New Haven
Hospital CUnic
Yale-New Haven
CUnic for abortion
Between initial
visit and abortion -
on same day for
first trimester cases
2/395
(0.5%)
Yale-New Haven
Hospital^ ^
Jan 1972
to May 1973
CUnic visit for
abortion
Abortion at same
cUnic
During the cUnic visit
30/3,887
(0.8%)
Baker and
Freeman'
1971
Private physicians
and direct applica-
tion to hospital
Grady Memorial
Hospital, Atlanta.
Georgia
Between contact with
abortion "coordinator"
and abortion procedure
33/341
(9.7%)t
British Pregnancy
Advisory Service
(BPAS)"
1971
BPAS counseling
and approval for
abortion
BPAS CUnic
for abortion
Between consultation
with 2 MDs who signed
a certificate approving
the abortion and
the procedure
248/16,088
(1.5%)
Preterm Boston^^
Aug 1, 1973
to
Dec 31, 1974
CUnic visit for
abortion
Abortion at same
clinic
During the cUnic visit
31/10,858
(0.3%)
London Pregnancy
Advisory Service
(LPAS)tt
Probably
1969-1970
Initial LPAS
interview
LPAS CUnic
for abortion
Between initial
interview and abortion
42/3,000
(1.4%)
Pare and Raven ■'
1962-1968
Psychiatric interview
and recommended
for abortion
St. Bartholomew's
Hospital. London
Between psychiatric
approval and abortion
2/130
(1.5%)
Eastern Women's
Center""
Feb 1 to
Aug 1, 1972
Clinic visit for
abortion
Abortion at same
cUnic
During the cUnic visit
6/9,820 §
(0.06%)
Eastern Women's
Center""
1973
CUnic visit for
abortion
Abortion at same
cUnic
During the cUnic visit
7/7,777 §
(0.09%)
♦Number of women changing mind over total number
recomputed for the current report.
eferred for abort
*It is unclear what proporti
before visiting the clinic
who decided not to abort did so following a telephone appointment but
!n who visited the clinic and then changed their mind.
tAn additional two women were listed as "rejection of system" and nine as a "minor unwilling or unable to obtain
(parental) consent." Inclusion of these women in the rate of those listed as "changed mind" increases it to 12.9%.
At follow-up only 27 of the 44 women not "aborting" were found to be pregnant (see text for details).
ttThese da
§These da
re reported as evidence to the Committee on the Wor)cing of the Abortion Act
elude women not aborted because of advanced gestation and other medical con
16-6
Several of the reported studies are from Britain '' ■' •' and these data
show a more uniform rate for changes in decision which range from 1.4 percent
to 2.2 percent. Even though abortions are performed under liberal laws in Bri-
tain a woman must have the consent of her physician before an abortion may be
performed. Contact with the physician may be a relatively uniform institutional
process which, in effect, filters out women who might otherwise be candidates
for later changing their decision to abort. Moreover, this process may account
for the similarity of the rates from the British data. In other respects, par-
ticularly their counseling and medical procedures, the larger scale British
abortion facilities, the London* and British^® Pregnancy Advisory Services, are
not unlike free standing abortion clinics in the United States. One wonders,
then, why the rates in changing the decision to abort are not more alike. For
example, the lowest available rate from the United States, 0.06 percent, is 23
times lower than the lowest British rate of 1.4 percent. One explanation may be
that data from the free standing facilities includes only women aborting in the
first trimester whereas the British data included second trimester patients.
The possible influence of gestation on changing the decision to abort will be
discussed in a later section.
Problems in Computing the Change in Decision Rate
The formula used to compute the rate for women who change their decision
to abort has been presented above. It is, of course, essential in computing the
rate to ensure that all the women in the numerator have also been listed in the
denominator and this has been done in Table 3. In comparing rates from different
abortion facilities one would like to be assured that criteria for entering the
numerator are the same across studies, as are criteria for entering the denomi-
nator.
Typically, women are identified who have "changed their mind" or who are
"having the baby." There has been no systematic attempt to adequately define
what is meant by a change in the decision, indeed there is no specific study
of the phenomenon of decision changes prior to abortion anywhere in the litera-
ture. Some of the data presented in this report have been culled from clinic
statistics and one can have little assurance that correct criteria for collecting
research data were completely followed. Other data have been determined from
reports of methodology and sampling in studies which were essentially dealing
with other research questions. Several studies ■'*' ^^ include an unknown propor-
tion of women who changed their decision to abort prior to reaching the clinic
among those women who did so after the clinic visit. In a sample from Yale-
New Haven Hospital some women who changed their decision to abort before visiting
the clinic are included-'^ whereas these women are not included in service statis-
tics from the same hospital which show a much lower rate^^ as does information
from the sampling frame for another study at the same hospital.^-'
In one study'® women who "rejected the system" and minors "unwilling or
unable to obtain (parental) consent" were not included with those who "changed
their mind." One cannot be confident, however, that such women would not have
been included in the numerator of other studies.
As we have seen, the characteristics of women entering the denominator,
that is women referred for abortion, have been influenced by different social,
legal and clinic policies. Women who are prescreened by physicians, excluded
because of advanced gestational age, or disinclined to request abortion because
of institutional policies, have been disproportionately excluded from some
studies rather than others.
CHARACTERISTICS OF WOMEN WHO MAY BE AT HIGHER RISK OF DECIDING NOT TO ABORT
Again it is useful to consider the period during which a woman might decide
not to abort in two stages; the time between suspicion of pregnancy and contact
at a clinic, and the period following personal contact at the clinic. There is
no evidence in the literature, nor from clinical impression, that tells us which
women have been more likely to change their decision to abort after making con-
tact with the abortion facility. Nonetheless, it is possible to paint some
picture, albeit an incomplete one, of women who are more likely to report, when
they finally do obtain an abortion, that they went through a period of indecision.
This evidence will be reviewed in the remainder of this section.
Evidence From Studies of Delayed Decisions to Abort
Indecision ,^^ increased conflict over the decision to abort^* (Table 1),
and delayed decisions to abort ^^' ^^' ^^ have been shown to be related to abortion
obtained in the second trimester. Women who have been shown to be significantly
more likely to delay in seeking abortion, therefore, might also be similar to
those who are more likely to change their decision to abort. There is a growing
body of information on the phenomenon of delayed abortion^" and only the major
correlates of delay will be reported here.
Women delaying in seeking induced abortion have been generally found to
be young,"' i''^''^2 single ,"•!'• ^9. 3i-33 pj-i^igravidas ,^^' ^®' ^^ and experiencing their
first abortion .3". 35 Black women have been found to be later presenters for
abortion,'^' ^^' ■'^ as have women from lower socioeconomic groups, '2' ^^ those with
lower levels of completed education, ■''• ^^ and women who are unemployed .•'^' ■'^' ^^
These observations should not suggest that the delay in seeking an abortion
results entirely, or even principally, from changes in the decision to abort.
Many of the women who delay in seeking abortion have been reported to at least be
partially delayed because of institutional hurdles in obtaining abortion ^3. i7, 29, 33, 36-38
or because of an unstable relationship with the partner"' ■'^' ■'^ or parents.''" Yet
another contributor to delayed abortion has been reported to be delay in recogni-
tion of pregnancy 11' 13, 17, 29, 32, 40, 41 ^y. denial of pregnancy .i''''*°
16-8
Evidence from Unpublished Data
In a study of the decision to seek induced abortion among samples of women
in New York and New Haven '^ respondents were asked "How many times did you change
your mind about having the abortion?" The responses have been shown in Table 1.
Indecision over the decision to abort was used as a dependent variable (dichot-
omized as never changed mind versus changed mind once or more) in order to rean-
alyze data from the study to examine the correlates of indecision prior to the
abortion.
When simple socioeconomic factors were considered, women who were younger,
less well educated and nulliparas were significantly more likely to report
indecision prior to abortion. In order to obtain a more complete picture of
the socio-demographic and psychological milieu in which indecision occurs the
New York data were analyzed using a stepwise multiple regression technique. The
first step in the regression analysis selected the single variable with the
greatest prediction on the dependent variable based on the simple correlations.
The second independent variable put into the regression equation was that which
provided the best prediction of the dependent variable in conjunction with the
first variable. Only independent variables making a significant contribution
(as measured by an F-test) when added to the other independent variables have
been presented in Table 4.
Table 4. Stepwise Multiple Regression Analysis of Changes in the Decision
to Abort by Selected Independent Variables, New York Sample (n = 345)
Step
Variable*
B
s.e.B
F
R
r2
r
1.
Difficulty in making
the decision to abort
.1220
.0246
24.70
.622
.387
.622
2.
Initially rejected
idea of abortion
.1148
.0282
16.59
.665
.442
.569
3.
Initially happy
about pregnancy
.0860
.0271
9.97
.692
.479
.437
4.
Nonsupportive relation-
ship with partner
.0829
.0393
4.46
.698
.487
.127
5.
More people know about
abortion decision
.0527
.0306
2.97
.■704
.495
.212
6.
Low ego resilience
.4544
.2715
2.80
.709
.503
.158
*Variables are described to indicate prediction of more frequent indecision
over decision to abort.
16-9
The six independent variables first entering the regression equation were
able to explain 50 percent of the variance in the dependent variable. None of
the demographic measures entered the regression equation, indeed the most power-
ful variables predicting indecision are ones reflecting the woman's psychological
reaction to the pregnancy and abortion, the level of support she is likely to
receive from her partner, the influence of many people knowing about the abortion
and the woman's ability to cope with conflict during the decision process as
measured by her ego resilience.
This analysis suggests, then, that changes in the decision to abort prior
to visiting the clinic are associated less with simple demographic variables
and more with psychological attributes which are less easily measured. Thus any
attempt to develop measures which would enable clinicians to improve their ability
to identify women who might change their decision to abort would have to include
factors operationalizing the kind of psychological parameters shown in Table 4.
The evidence presented above may be summarized as follows. There is fairly
substantial agreement, in the literature, on the demographic characteristics of
women who have delayed abortion procedures . There has been less success in iden-
tifying women who delay making decisions to abort independent of other factors
which may cause delayed abortion. Furthermore, there is some evidence that
delayed abortion is associated with indecision to abort and this will be discus-
sed more thoroughly in the next section.
It is quite obvious that a good deal of further investigation is required
to confirm the rather tenuous relationships which emerge out of the currently
available research findings. Moreover, it is important to emphasize that there
is nothing in the available literature to indicate that women who are indecisive
about their abortion prior to reaching the clinic will also continue to be inde-
cisive after visiting the clinic. It could be argued that women who are indeci-
sive during the earlier stages of their decision to abort might be more likely
to continue to be indecisive until the abortion is performed, and, indeed, even
after the abortion . ^^' "^ Alternatively, women who pass through an indecisive
period prior to visiting the clinic and then resolve the decisional conflicts
may be least likely to change their decision to abort after visiting the clinic.
There is evidence in the psychological literature for both points of view^'' and
few, if any, clinical reports speak to the issue.
Possibly other parameters, such as the woman's ability to cope with
conflict, her self-esteem, feelings of powerlessness , and so on, will be more
important indicators of late changes in the decision to abort than will a simple
measure of how indecisive a woman was during her pre-clinic decision making.
In one study^* women of low ego resilience delayed relatively less in seeking
abortion when the decision was highly conflictful than women of higher ego resil-
ience. One explanation of this unexpected finding is that women who are better
able to cope with the distress of having to decide to abort (the high ego resil-
ience group) delay with increased conflict because they use the time to resolve
conflicting issues which may produce indecisiveness . Women who cannot cope
with the conflict of decision making may have truncated their decision processes
in order to avoid the stress and anxiety of decisional conflicts and thus they
will not resolve their indecisiveness. Such women are much more likely to be
prone to changing their abortion decision after arrival at the clinic and when
they are faced with new considerations in their decision for which they were
not prepared. Some of the possible factors which may change the woman's deci-
sion at this stage are discussed below.
PSYCHOLOGICAL AND SITUATIONAL FACTORS WHICH MIGHT CONTRIBUTE TO A CHANGE IN
THE DECISION TO ABORT
Here we consider a number of factors which might contribute to a change in
the decision to abort. In the previous section it was postulated that an important
determinant of late changed decisions could be the failure to resolve conflicting
issues (rather than simply the presence of conflict) in the earlier decision-
making stages. When late changes in the decision to abort occur the full ramifi-
cations of the decision to abort may not have been thought through making the
decision vulnerable to new (possibly, even trivial) pieces of information which
change the decisional "balance sheet" in favor of the delivery option.
The concept of "balanced decision" hints at a psychosocial concept of
decision making which has been more fully developed by Janis and Mann""''*^ and
described in terms of decision making during unwanted pregnancy elsewhere .-^^
It has been proposed that during the decision to abort a woman passes through
five stages. She must (1) acknowledge that she is pregnant, (2) consider the
options, abortion or delivery, which are open to her, (3) consider the advan-
tages and disadvantages of abortion or delivery by scanning and weighing the
pros and cons of each alternative, (4) commit herself to one particular option,
and (5) adhere to the decision.
Stage 3, when the pros and cons of abortion are considered, is of partic-
ular relevance to the Commission's interest since the degree of effort put into
considering all information pertinent to the decision at this stage will "influ-
ence the long-run stability of the decision. ""^ Thus a new piece of information
during Stage 5 is only likely to result in a changed decision if it has not been
anticipated and if contingency plans (both utilitarian and psychological) have
not been prepared during Stage 3. For example, women who have sought informa-
tion about abortion techniques, say by asking their physician, friends or by
reading, are less likely to decide not to abort when the abortion procedures
are described at the clinic. Improvement in the early decision-making process,
according to this formulation, will reduce the risk of later indecision.
This brief description of the psychosocial concept of decision making
under conflict does violence to a rather complicated theory based on a consid-
erable amount of psychological evidence. It is sufficient, however, to make
the point that the process of decision making is likely to be a more powerful
predictor of later changes in the decision than is any one particular group of
variables. Thus the search for situational factors which might contribute to
a late decision not to abort is likely to be an elusive one.
The above discussion notwithstanding, four issues will be considered as
having some likelihood of influencing the probability that a woman might change
her decision to abort. These are (1) the gestational age of the pregnancy,
(2) social and psychological considerations, (3) abortion counseling at the
clinic, and (4) participation in a research project at the clinic.
16-11
Gestational Age of Pregnancy
There is some indication that increased gestational age is correlated with
increased conflict during the decision process prior to arriving at the clinic
(Table 1)^^ and a more difficult decision to abort ."• ^^' ■'"• ^^' ■'^ Here, however,
we are more concerned with the influence of gestation on a change in the decision
to abort after visiting the clinic. Three considerations might contribute to
late changes in the abortion decision. First, with later gestation, the abortion
client may have experienced fetal movement which results in an increased emotional
investment in the fetus. While the experience of fetal movement would be more
likely to influence preclinic decisional change than it would be to produce a
change in decision during the clinic visit itself, experience of fetal movement
might be an important factor in influencing other considerations that do occur
during the clinic visit.
Second, it would seem reasonable to propose that the principal influence
of later gestation is on the change in the abortion procedure demanded by a
second trimester pregnancy. It is likely that most women are unaware of the
different abortion procedures for first and second trimester abortion until they
arrive at the clinic. The second trimester procedure (usually saline instilla-
tion) has an approximately four-fold increased risk of major complications^^ and
a seven- to nine-fold increased risk of death ^^ and, on being confronted with a
more serious procedure than expected, women who have not made a firm decision to
abort may decide to deliver. Furthermore, the second trimester abortion proce-
dure is more expensive *^' ''^ and requires an overnight hospital stay — considera-
tions which might also be sufficient to change the decision in favor of not
aborting.
Very few of the studies reported in Table 3 indicate the proportion of
first trimester abortion patients who change their decision versus those in the
second trimester. However, samples with the larger proportion of second trimes-
ter women are also those with a larger rate of decisional change. At Grady Memor-
ial Hospital'® 26.7 percent and at Yale-New Haven Hospital^-' 24.2 percent were in
the second trimester. The data from the British Pregnancy Advisory Service^' and
King's College Hospital'® indicate that 20 percent and 14.5 percent respectively
were referred for abortion in the second trimester. Both of the women in the
Yale-New Haven study sample'' who decided to deliver were in the second trimester.
The three large free-standing abortion clinics represented in Table 3 only
include first trimester procedures .'^' ^°' ^'
The third consideration results from the fact that women who present for
abortion between the twelfth and fifteenth week of gestation are often asked to
return beyond the fifteenth week because that is the optimal period for instil-
lation procedures. There is neither empirical nor clinical documentation of the
number of women who may, during this potentially vulnerable period, decide not
to abort. Women who are refused abortion (many during the first telephone con-
tact) because of advanced gestation at first trimester abortion clinics must
often reregister for a second trimester abortion at another hospital. Records
of the outcome of denied applications have not been maintained.
Of acute interest is the final pregnancy decision of women who visit a
clinic or hospital abortion facility and who are only told following a medical
examination that they are too advanced in pregnancy for a first trimester
16-12
procedure. These women are at risk of being asked to participate in research
projects. While many first trimester abortion clinics maintain very close rela-
tionships with hospitals performing second trimester procedures, no data have
been found which indicate what proportion of women denied first abortion do go
on to abort in the second trimester. Some estimate of the prevalence of denied
abortion because of advanced gestation is indicated by the data in Table 5.
Table 5. The Number and Proportion of Women Refused First
Trimester Abortions Because of Advanced Gestational Age
Source
Year
Number
Refused
Total Refused ^, ^^^
Total Keeping Appointment
Erie Medical Center
1973
658
9.7
Buffalo, New York^^
1974
658
6.8
Eastern Women's Center
Feb 1 to
454
18.6
New York^°
Aug 1, 1972
1973
553
15.1
Jan 1 to
294
15.0
Oct 31, 1974
Social and Situational Factors
In this section a number of issues which emerge from the literature and
which have not been previously considered are briefly discussed in terms of
their implication for a change in the decision to abort.
A number of factors have been considered to contribute to conflict during
pregnancy. Much of this research has dealt with "wanted" pregnancy and the fac-
tors include: hyperemesis ,*8 common antenatal problems ,''5 attitudes toward
feminine role,^°'^i sexual attitudes toward mother, father, and husband, ^^ "sick
role" expectations in pregnancy, 53 and rejection of the pregnancy by the father
and experience of having a previously defective or deformed child .^'* All of the
above factors might be considered, if they occur during a pregnancy which is not
unequivocally wanted, to contribute to an unchanged decision to abort. Evidence
from studies of the reasons for seeking induced abortion also suggest situations
in which the abortion decision is likely to remain firm. Among the more impor-
tant are : social sanctions faced by single women who do not renounce mother-
hood,^i-^s inability to manage another child, 55-57 and anxiety over deformity of
the child .55
The same body of literature suggests a number of situations which, in the
absence of hard data can only lead us to speculate, may be associated with a
changed decision to deliver and not abort either before or during the clinic
visit. These include: deviant scores on psychological tests ,^® emotional
immaturity,^' attempts to involve the partner in marriage ,^®' ^^' ^° inadequate
emotional supports,*^ mental abnormality,'^®-^' previous psychiatric dif f iculty ,^®' ^^
and anxiety of the abortion procedure itself or surgery in general.®^
Abortion Counseling
Much of the early literature was written at a time when abortion "coun-
seling" consisted of an interview during which the abortion applicant had to
convince a psychiatrist that abortion was necessary for her mental, if not
physical health. Reviewers of this literature^''"®® have pointed out the biases
inherent in findings from that research. In this section we are concerned with
the influence of abortion counseling as it currently is practiced in many abor-
tion clinics in the United States .23-26, 67-69
The essential feature of abortion counseling, as expressed by almost all
writers and most pertinent for this inquiry, is that aspect of counseling in
which the counselor determines the nature of the abortion client's decision-
making process. The review of the pros and cons of the decision to abort,
including an examination of any conflicts in the decision and how they were
resolved, enables the counselor to assess the "quality" of the decision pro-
cess. Particularly important, is whether the abortion client denied, negated
or used other ego defense mechanisms leading her to ignore areas of conflict
during the decision making which might result in an increased risk of post-
decisional regret after the abortion. This type of counseling rarely leads to
a unilateral decision on the part of the counselor to deny the client an abor-
tion but, most frequently, the abortion client herself realizes during coun-
seling that she is not yet prepared to commit herself to having an abortion.
It was reported that the 31 women who decided not to abort while at Preterm in
Boston (Table 3),27 did so during extensive individual counseling with trained
abortion counselors.
Abortion counseling, then, is a crucial process for screening out appli-
cants for abortion who might be at higher risk for changing their decision to
abort prior to the procedure itself.
Participation in Research Projects
In order to gain some insight into the possible effect of participation
in research prior to abortion on the decision to abort it is again useful to
consider the "balance-sheet" model of decision making. At least two issues
must be considered: (a) the extent to which a decision to abort is balanced
in favor of abortion, and (b) the nature of the research activity itself.
Women who are firmly committed to aborting (either because the factors in
their decision were heavily weighted toward abortion or because decisional con-
flicts were successfully resolved in favor of abortion) are unlikely to change
that decision because of participation in a research project. For these women,
participation in research is most likely to become yet another component in
their decisional balance sheet which either reinforces an existing decision to
abort or (for some types of research discussed below) favors delivery but is
not a powerful enough cognition to counterbalance other factors favoring abor-
tion.
What, however, of the woman who is less certain of her decision to seek
abortion? In the absence of empirical data on the issue we must turn to some
of the psychological literature for guidance. A woman who is generally disposed
against abortion and yet finds herself in a clinic preparing for an abortion
procedure is experiencing cognitive dissonance .^°"^^ In speculating on the
effect of participation in research on this situation it would seem reasonable
to expect that the nature of the research activity itself would influence the
decision. Research which emphasized the viability or "humanity" of the fetus
might be sufficient to induce a change in the decision to abort. Other research,
which had some element of risk to the fetus and therefore of giving birth to a
deformed baby, would reduce the likelihood of a change in the decision to abort.
In one Hungarian study ^'^ 327 women were examined by ultrasonic Doppler
technique within one hour of a requested first trimester abortion. The study
sought to determine the efficiency of the Doppler technique, which has no risk
to the fetus, in detecting fetal heart beats at various stages of pregnancy.
While patients were not told the purpose of the ultrasonic Doppler examination,
over 90 percent of the patients associated the audible sounds with the fetal
heart. The reaction of the patients, especially the multigravidas , on listening
to the fetal heart sounds is of interest here. Among the multigravidas 60 per-
cent were reported very disturbed by the sounds and immediately went into a
long explanation rationalizing their decision to seek abortion to the medical
staff. A further 16 percent changed their minds about the abortion and decided
to bear the pregnancy to term. Among primigravidas 30 percent were disturbed
by the experience and an additional 2 percent decided not to abort.
The report of this study does not indicate whether women were counseled
prior to their abortion. Nor, beyond knowing that patients were not told to
expect fetal heart sounds, are the consent procedures described. However,
irrespective of steps taken to obtain informed consent, one must deplore the
callous disregard shown the patient by leaving the instrument within such close
proximity to her that it could be overheard.
The Hungarian study primarily emphasizes the importance of ensuring that
all patients asked to participate in research projects have been independently
counseled to provide assurances that a firm decision to abort has been reached.
The study also indicates the need to avoid research maneuvers which violate
the particular sensibilities of preabortion patients. The Hungarian study
neither sheds light on the effect of fetal research which does not raise con-
flict over the decision to abort nor on research which, because of increased
risk to the fetus, further supports the decision to abort.
16-15
Participation in research which has some risk to the fetus might be con-
sidered to reduce the choice which still remains for abortion or delivery.
Evidence from psychological laboratories^'' ^^' ^^ suggests that the reduction of
choice in a decision also reduces cognitive dissonance. These data imply, then,
that participation in a higher risk fetal research project would incline the
more ambivalent abortion patient toward a firmer decision to abort. Addition-
ally, it might be argued, that only a relatively severe threat, such as fetal
research involving drugs, would enhance an existing decision to abort. Less
innocuous procedures, say the completion of questionnaires, might simply increase
cognitive dissonance in the ambivalent patient^^ and act as an additional factor
against the abortion decision.
1. Little available research has directly confronted the question of change in
the decision to abort which is reviewed in this paper. All the evidence is
drawn, second hand, from a variety of sources in which other issues were the
object of interest. There is a clear demand for hard empirical data in this
area.
2. Among women who abort as many as one third report having changed their deci-
sion to abort at least once prior to reaching the clinic. Difficult decisions
and conflict during decision making are also quite prevalent.
3. Approximately 10 percent of appointments for abortion are not kept, a figure
which probably overestimates the proportion of women who have decided to
deliver.
4. In large volume free-standing clinics aborting women in the first trimester
in the present socio-legal climate, less than 1 percent of abortion appli-
cants are likely to decide not to abort after visiting the clinic. In
facilities offering second trimester procedures it is unlikely that more
than 2 percent of applicants will change their mind.
5. Women more at risk of changing their decision to abort are more likely to be
characterized by psychological than by demographic factors. The style of
coping with conflicts during decision making, rather than simply the presence
of conflict, is more likely to predict late changes of decision.
6. Women aborting in the second, versus first, trimester may be at relatively
greater risk of changing their decision to abort.
7. Between 5 percent and 20 percent of women examined at clinics performing
first trimester procedures are refused abortion because of advanced gesta-
tional size. At other hospitals an unrecorded number of women have their
abortion postponed because they are between 13 and 15 weeks pregnant. For
either group of women there is no indication what proportion eventually go
on to abort. In the absence of information to the contrary these women must
be considered at elevated risk of changing their decision to abort.
8. Abortion counseling is a crucial procedure for selecting out of the clinic
population women who are at increased risk of changing their decision to
abort. An invitation to participate in a research project should only fol-
low, and should be independent of, routine abortion counseling.
9. Women who have reached a firm decision to abort are unlikely to change their
decision because of participation in a research project. Women more ambiva-
lent about aborting are only likely to change their decision if the research
maneuvers emphasize the viability of, and present no risk to, the fetus.
16-17
REFERENCES
1. Pare, C.M.B. and Raven, H., "Follow-up of Patients Referred for Termination
of Pregnancy," Lancet 1:635-641, 1970.
2. Figa-Talamanca, I., "Induced Abortion in Italy," Pacific Health Education
Reports 4:1-139, 1974.
3. Stampar, D. , "Croatia: Outcome of Pregnancy in Women l-Jhose Requests for
Abortion Have Been Denied," Studies in Family Planning 4:267-269, 1973.
4. Armijo, R. and Monreal, T. , "Epidemiology of Provoked Abortion in Santiago,
Chile," Journal of Sex Research 1:143, 1965.
5. Armijo, R. and Monreal, T. , "The Problem of Induced Abortion in Chile,"
Milbank Memorial Fund Quarterly 43:263, 1965.
6. Committee on the Working of the Abortion Act, Volume 2, Statistical Volume,
London, Her Majesty's Stationery Office, 1974.
7. Weinstock, E., Tietze, C, Jaffe, F.S., et al., "Legal Abortions in the
United States Since the 1973 Supreme Court Decisions," Studies in Family
Planning 7:23-31, 1975.
8. Roe V. Wade, 410 U.S. 113 (1973); and Doe v. Bolton, 410 U.S. 179 (1973).
9. Pohlman, E., The Psychology of Birth Planning, Cambridge, Mass.: Schenkman,
1969.
10. Diamond, M., Steinhoff, P.G., Palmore, J. A., et al. , "Sexuality, Birth Con-
trol and Abortion: A Decision-Making Sequence," Journal of Biosocial
Science 5:347-361, 1973.
11. Bracken, M.B., An Epidemiological Study of Psychosocial Correlates of Delayed
Decisions to Abort, Ph.D. Dissertation, Yale University, 1974.
12. Osofsky, J.D., Osofsky, H.J., and Rajan, R. , "Psychological Effects of Abor-
tion: With Emphasis Upon Immediate Reactions and Follow-Up," The Abortion
Experience, Osofsky, H.J. and Osofsky, J.D. (eds) , Hagerstown, Maryland:
Harper and Row, 1973.
13. Kerenyi, T.D., Glascock, E.L., and Horowitz, M.L. , "Reasons for Delayed
Abortion: Results of Four Hundred Interviews," American Journal of
Obstetrics and Gynecology 117:299-311, 1973.
16-18
REFERENCES (Continued)
14. Bracken, M.B. and Kasl, S.V., "Denial of Pregnancy, Conflict, and Delayed
Decisions to Abort," Proceedings of the Fourth International Congress of
Psychosomatic Obstetrics and Gynecology, S. Karger, Basel, 1975 (In Press).
15. Nathanson, R.N., "Ambulatory Abortion: Experience with 26,000 Cases
(July 1, 1970 to August 1, 1971)," New England Journal of Medicine
286:403-407, 1972.
16. Newton, J., Brotman, M. , McEwen, J., et al., "Hospital Family Planning:
Termination of Pregnancy and Contraceptive Use," British Medical Journal
4:280-284, 1973.
17. Bracken, M.B. and Swigar , M.E. , "Factors Associated with Delay in Seeking
Induced Abortions," American Journal of Obstetrics and Gynecology
113:301-309, 1972.
18. Baker, L.D. and Freeman, M.G. , "Statistical Analysis of Applicants and of
the Induced Abortion Work-Up," Journal of the Medical Association of
Georgia 60:392-396, 1971.
19. British Pregnancy Advisory Service, Client Statistics for 1971, BPAS,
Birmingham, England, 1973, p. 7.
20. Eastern Women's Center, statistics provided for the New York City Board of
Health, 1972 and 1973, and personal communication.
21. Yale-New Haven Hospital, Service Statistics, 1973, and personal communication.
22. Hausknecht, R.U. , "Free Standing Abortion Clinics: A New Phenomenon,"
Bulletin of the New York Academy of Medicine 49:985-991, 1973.
23. Asher, J.D. , "Abortion Counseling," American Journal of Public Health
62:686-688, 1972.
24. Bracken, M.B., Grossman, G., Hachamovitch, M. , et al., "Abortion Counseling:
An Experimental Study of Three Techniques," American Journal of Obstetrics
and Gynecology 117:10-20, 1973.
25. Butler, J.L. and Fujita, B.N., "Abortion Screening and Counseling: A Brief
Guideline for Physicians," Postgraduate Medicine 50:208-212, 1971.
25. Keller, C. and Copeland, P., "Counseling the Abortion Patient is More than
Talk," American Journal of Nursing 72:102-109, 1972.
27. Preterm Boston, Clinic Statistics provided by personal communication with
Dr. Philip Stubblef ield. Clinic Director.
28. Erie Medical Center, Buffalo, New Yorlc, Clinic Statistics and personal
Communication .
16-19
REFERENCES (Continued)
29. Mallory, A.B., Rubenstein, L.Z., Drosness, D.L., et al., "Factors Responsible
for Delay in Obtaining Interruption of Pregnancy," Obstetrics and Gynecologu
40:556-562, 1972.
30. Bracken, M.B. and Kasl, S.V., "Delay in Seeking Induced Abortion: A Review
and Theoretical Analysis," American Journal of Obstetrics and Gynecology
April 1, 1975, p. 1008.
31. Tietze, C. and Lewit, S., "Joint Program for the Study of Abortion (JPSA) :
Early Medical Complications of Legal Abortion," Studies in Family Planning
3:97-124, 1972.
32. Johnson, F.D. and Vincent, L. , "Factors Affecting Gestational Age at Termination
of Pregnancy," Lancet ii: 717-719, 1973.
33. Chalmers, I. and Anderson, A., "Factors Affecting Gestational Age at Therapeutic
Abortion," Lancet 1:1324-1326, 1972.
34.
36.
38.
39.
42.
Bracken, M.B., Hachamovitch, M. , and Grossman, G., "Correlates of Repeat
Induced Abortions," Obstetrics and Gynecology 40:816-825, 1972.
35. Bracken, M.B. and Kasl, S.V., First and Repeat Abortions: A Study of Decision-
Making and Delay (In Press) .
Ingham, C. and Simms, M. , "Study of Applicants for Abortion at the Royal
Northern Hospital, London," Journal of Biosocial Science 4:351-369, 1972.
37. Cartwright, A. and Waite, M. , "General Practitioners and Abortion, Evidence
to the Committee on the Working of the Abortion Act," Royal College of
General Practitioners Journal 22 (No. 1) , 1972.
Cartwright, A. and Lucas, S., Report of the Committee on the Working of the
Abortion Act, Volume III, Survey of Abortion Patients, London, Her Majesty's
Stationery Office, 1974.
Oppel, W., Athanasiou, R. , Cushner, I., et al., "Contraceptive Antecedents to
Early and Late Therapeutic Abortions," American Journal of Public Health
62:824-827, 1972.
Kaltreider, N.B. , "Emotional Patterns Related to Delay in Decisions to Seek
Legal Abortion," California Medicine 118:23-27, 1973.
Grauer, H., "A Study of Contraception as Related to Unwanted Pregnancy,"
Canadian Medical Association Journal 107:739-741, 1972.
Bracken, M.B., Hachamovitch, M. , and Grossman, G. , "The Decision to Abort
and Psychological Sequelae," Journal of Nervous and Mental Disease
158:154-162, 1974.
16-20
REFERENCES (Continued)
43. Bracken, M.B., "Abortion Attitudes and Discrepant Behavior: Some Theoretical
Issues," Health Education Journal 32:4-9, 1973.
44. Janis, I.L., "Stages in the Decision-Making Process," Abelson, R.P., et al. ,
(eds) Theories of Cognitive Consistency , A Sourcebook, Chicago: Rand
McNally, 1968.
45. Janis, I.L. and Mann, L. , "A Conflict Theory Approach to Attitude Change and
Decision-Making," Greenwald, A. (ed) , Psychological Foundations of Attitudes,
New York: Academic Press, Inc., 1968.
46. Berger, G.S., Tietze, C, Pakter, J., et al., "Maternal Mortality Associated
With Legal Abortion in New York State: July 1, 1970- June 30, 1972,"
Obstetrics and Gynecology 43:315-326, 1974.
47. Muller, C.F. and Jaffe, F.S., "Financing Fertility Related Health Services
in the United States, 1972-1978: A Preliminary Projection," Family Planning
Perspectives 4 (No. 1):6-19, 1972.
48. Hanford, J.M. , "Pregnancy as a State of Conflict," Psychological Reports
22:1313-1342, 1968.
49. Hetzel, B.S., Bruer, B. , and Poidevin, L.O.S., "A Survey of the Relation
Between Certain Common Antenatal Complications in Primiparae and Stressful
Life Situations During Pregnancy," Journal of Psychosomatic Research 5: 175-182,
1961.
50. Kapp, F.T., Hornstein, S., and Graham, V. J. , "Some Psychologic Factors in
Prolonged Labor Due to Inefficient Uterine Action," Comprehensive Psychiatry
4:9-18, 1963.
51. Deutsch, H. , The Psychology of Women 2, New York: Grune a Stratton, 1945.
52. Weil, R.J. and Tupper, C. , "Personality, Life Situation and Communication:
A Study of Habitual Abortion," Psychosomatic Medicine 22:448-455, 1960.
53. Brown, L.B., "Social and Attitudinal Concomitants of Illness in Pregnancy,"
British Journal of Medical Psychology 35:311-322, 1962.
54. Helper, M.M. , Cohen, R.L., Beitenman, E.T., et al., "Life-Events and Acceptance
of Pregnancy," Journal of Psychosomatic Research 12:183-188, 1968.
55. Clark, M. , et al., "Sequels of Unwanted Pregnancy," Lancet 2:501-507, 1968.
56. Ekblad, M. , "Induced Abortion on Psychiatric Grounds: A Follow-Up Study of
479 Women," Acta Psychiatrica Scandinavica 31:99, 1955.
57. Jansson, B. , "Mental Disorders after Abortion," Acta Psychiatrica Scandinavica
41:108, 1965.
REFERENCES (Continued)
58. Davids, A. and Rosengren W. , "Social Stability and Psychological Adjustment
During Pregnancy," Psychosomatic Medicine 24:579-583, 1962.
59. Davids, A., Holden, R.H., and Gray, G.B., "Maternal Anxiety During Pregnancy
and Child Adjustment Eight Months Following Childbirth," Child Development
34:993-1002, 1963.
60. Kimball, C.P., "Some Observations Regarding Unwanted Pregnancies and Thera-
peutic Abortions," Obstetrics and Gynecology 35:293-296, 1970.
61. Hook, K. , "Refused Abortion," Acta Psychiatrica Scandinavica 39:168, 1963.
62. Beauvoir, S. de.. The Second Sex, Parshley, H.M. (Trans), New York: Bantam
Books, 1961.
63. Janis I.L., Psychological Stress: Psychoanalytic and Behavioral Studies of
Surgical Patients, New York: John Wiley S Sons, 1968.
64. Sloane, R.B. , "The Unwanted Pregnancy," New England Journal of Medicine
280:1206-1213, 1969.
65. Callahan, D. , Abortion: Law, Choice and Morality , London: McMillan, 1970.
66. Walter, G.S., "Psychological and Emotional Consequences of Elective Abortion,"
Obstetrics and Gynecology 36:482-491, 1970.
67. Lieberman, E.J. "Abortion Counseling," Lewit, S. (ed) , "Abortion Techniques
and Services," Amsterdam, Excerpta Medica, 1972.
68. Whittington, H.G. , "Role of the Counselor in Abortion," Abortion Techniques
and Services , Ibid.
69. Branch, B.N. , "Counseling in Abortion Services," Abortion Techniques and
Services , Ibid.
70. Heider, F. , The Psychology of Interpersonal Relations, New York: Wiley, 1958.
71. Rosenberg, M.J. , "Cognitive Reorganization in Response to the Hypnotic Reversal
of Attitudinal Effect," Journal of Personality 28:39-63, 1960.
72. Festinger, L. , A Theory of Cognitive Dissonance , Stanford: Stanford University
Press, 1957.
73. Aronson, E., "The Theory of Cognitive Dissonance: A Current Perspective,"
Berkowitz, L. (ed) , Advances in Experimental Social Psychology, Vol. 4,
New York: Academic Press, 1969.
16-22
REFERENCES (Continued)
74. Szontagh, F.E., "Psychic Motives in the Decision of Women Requesting Induced
Legal Abortion," Morris, N. (ed) , Psychosomatic Medicine in Obstetrics and
Gynecology, Basel, Switzerland: S. Karger , 1972.
75. Aronson, E. and Carlsmith , J.M. , "The Effect of Severity of Threat on the
Devaluation of Forbidden Behavior," Journal of Abnormal and Social Psychology
66:584-588, 1963.
76. Freedman, J.L., "Preference for Dissonance Information," Journal of Personality
and Social Psychology 2:287-289, 1965.
77. Festinger, L. and Carlsmith, J., "Cognitive Consequence of Forced Compliance,"
Journal of Abnormal and Social Psychology 58:203-210, 1959.
78. Lerner, R.L., Bruce, J., Ochs, J.R. , et al., "Abortion Programs in New York
City: Services, Policies, and Potential Health Hazards," Health Society,
Winter, 1974, pp. 15-38.
r
Part II
SUPPLEMENTAL RESOURCE INFORMATION
^
17
THE NUREMBERG CODE OF ETHICS
IN MEDICAL RESEARCH
The Nuremberg Code of Ethics
in Medical Research
(1) The voliintary consent of the human siibject is absolutely essential.
This means that the person involved should have legal capacity to give consent:
should be so situated as to be able to exercise free power of choice without
the intervention of any element of force, fraud, deceit, duress, overreaching,
or other ulterior form of constraint or coercion and should have sufficient
knowledge and comprehension of the elements of the subject matter involved as
to enable him to make an understanding and enlightened decision. This latter
element requires that before the acceptance of an affirmative decision by the
experimental siibject there should be made known to him the nature, duration,
and purpose of the experiment; the method and means by which it is to be con-
ducted; all inconveniences and hazards reasonably to be expected; and the
effects upon his health or person which may possibly come from his participation
in the experiment.
The duty and responsibility for ascertaining the quality of the consent
rests upon each individual who initiates, directs, or engages in the experiment.
It is a personal duty and responsibility which may not be delegated to another
with impunity.
(2) The experiment should be such as to yield fruitful results for the
good of society, unprocurable by other methods or means of study, and not ran-
dom and unnecessary in nature.
(3) The experiment should be so designed and based on the results of
animal experimentation and a knowledge of the natural history of the disease or
other problem under study that the anticipated results will justify the perfor-
mance of the experiment.
(4) The experiment should be so conducted as to avoid all unnecessary
physical and mental suffering and injury.
(5) No experiment should be conducted where there is an a priori reason
to believe that death or disabling injury will occur; except, perhaps, in those
experiments where the experimental physicians also serve as subject.
(6) The degree of risk to be taken should never exceed that determined
by the humanitarian importance of the problem to be solved by the experiment.
17-1
(7) Proper preparations should be made and adequate facilities provided
to protect the experimental subject against even remote possibilities of injury,
disability, or death.
(8) The experiment should be conducted only by scientifically qualified
persons. The highest degree of skill and care should be required through all
stages of the experiment of those who conduct or engage in the experiment.
(9) During the course of the experiment the human subject should be at
liberty to bring the experiment to an end if he has reached the physical or
mental state where continuation of the experiment seems to him to be impossible.
(10) During the course of the experiment the scientist in charge must be
prepared to terminate the experiment at any stage, if he has probable cause to
believe, in the exercise of the good faith, superior skill, and careful judgment
required of him, that a continuation of the experiment is likely to result in
injury, disability, or death to the experimental subject.
DECLARATION OF HELSINKI
(Recommendations Guiding Doctors in Clinical Research
Adopted by the World Medical Association in 1964)
Declaration of Helsinki
INTRODUCTION
It is the mission of the doctor to safeguard the health of the people.
His knowledge and conscience are dedicated to the fulfillment of this mission.
The Declaration of Geneva of The World Medical Association binds the doctor
with the words: "The health of my patient will be my first consideration" and
the International Code of Medical Ethics which declares that "Any act or advice
which could weaken physical or mental resistance of a human being may be used
only in his interest."
Because it is essential that the results of laboratory experiments be
applied to human beings to further scientific knowledge and to help suffering
humanity, The World Medical Association has prepared the following recommen-
dations as a guide to each doctor in clinical research. It must be stressed
that the standards as drafted are only a guide to physicians all over the world.
Doctors are not relieved from criminal, civil and ethical responsibilities under
the laws of their own countries.
In the field of clinical research a fundamental distinction must be rec-
ognized between clinical research in which the aim is essentially therapeutic
for a patient, and the clinical research, the essential object of which is purely
scientific and without therapeutic value to the person subjected to the research.
I. BASIC PRINCIPLES
1. Clinical research must conform to the moral and scientific principles
that justify medical research and should be based on laboratory and animal experi-
ments or other scientifically established facts.
2. Clinical research should be conducted only by scientifically qualified
persons and under the supervision of a qualified medical man.
3. Clinical research cannot legitimately be carried out unless the impor-
tance of the objective is in proportion to the inherent risk to the subject.
4. Every clinical research project should be preceded by careful assess-
ment of inherent risks in comparision to forseeable benefits to the subject or
to others.
5. Special caution should be exercised by the doctor in performing clini-
cal research in which the personality of the subject is liable to be altered by
drugs or experimental procedure.
II. CLINICAL RESEARCH COMBINED WITH PROFESSIONAL CARE
1. In the treatment of the sick person, the doctor must be free to use a
new therapeutic measure, if in his judgment it offers hope of saving life,
reestablishing health, or alleviating suffering.
If at all possible, consistent with patient psychology, the doctor should
obtain the patient's freely given consent after the patient has been given a
full explanation. In case of legal incapacity, consent should also be procured
from the legal guardian; in case of physical incapacity the permission of the
legal guardian replaces that of the patient.
2. The doctor can combine clinical research with professional care, the
objective being the acquisition of new medical knowledge, only to the extent
that clinical research is justified by its therapeutic value for the patient.
III. NON-THERAPEUTIC CLINICAL RESEARCH
1. In the purely scientific application of clinical research carried out
on a human being, it is the duty of the doctor to remain the protector of the
life and health of that person on whom clinical research is being carried out.
2. The nature, the purpose and the risk of clinical research must be
explained to the subject by the doctor.
3a. Clinical research on a human being cannot be undertaken without his
free consent after he has been informed; if he is legally incompetent, the con-
sent of the legal guardian should be procured.
3b. The subject of clinical research should be in such a mental, physical
and legal state as to be able to exercise fully his power of choice.
3c. Consent should, as a rule, be obtained in writing. However, the
responsibility for clinical research always remains with the research worker;
it never falls on the subject even after consent is obtained.
4a. The investigator must respect the right of each individual to safe-
guard his personal integrity, especially if the subject is in a dependent rela-
tionship to the investigator.
4b. At any time during the course of clinical research the subject or
his guardian should be free to withdraw permission for research to be continued.
The investigator or the investigating team should discontinue the research
if in his or their judgment, it may, if continued, be harmful to the individual.
We, the undersigned medical organizations , endorse the ethical principles
set forth in the Declaration of Helsinki by the World Medical Association con-
cerning human experimentation. These principles supplement the principles of
medical ethics to which American physicians already subscribe .
American Federation for Clinical Research
American Society for Clinical Investigation
Central Society for Clinical Research
American College of Physicians
American College of Surgeons
Society for Pediatric Research
American Academy of Pediatrics
American Medical Association
18-3
19
THE USE OF FETUSES AND
FETAL MATERIAL FOR RESEARCH
Report of the Advisory Group,
Chaired by Sir John Peel, London, 1972
MEMBERS OF THE ADVISORY GROUP INCLUDE:
Sir John Peel, KCVO FRCOG FRCS FRCP (Chairman)
Miss H. S. Brett, SRN
Miss A. Catford, AIMSW
Dr. Christopher Clayson, OBE MD PRCP(E) FRCP (London) DPH
Mr. G. Prys Davies, OStJ LLM
Dr. G. S. Dawes, FRS DM FRCOG
Mr. G. S. Gimson, GC
Mrs. J. J. Godwin-Austen, SRN
Sir Harold Himsworth, KCB FRS FRCP MD
Dr. Pauline M. Jackson, MB BS DCH
His Honour Judge E. B. McLellan
The Use of Fetuses and Fetal Material
for Research
INTRODUCTION
1. We were appointed by the Secretary of State for Social Services and the
Secretaries of State for Scotland and Wales on 19 May 1970, with the following
terms of reference:
"To consider the ethical, medical, social and legal implications
of using fetuses and fetal material for research."
Number of Meetings
2. We held our first meeting on 30 July 1970 and we have met six times alto-
gether .
Evidence
3. Factual information on the use of human fetuses and fetal material for
research was obtained from the Medical Research Council and the Public Health
Laboratory Service. This is summarized in later sections of the report. In
addition to this evidence a number of organizations were invited to comment on
the matters within the terms of reference and we received some spontaneous
representations.
4. While there were differences of opinion in the evidence we were impressed
by the substantial measure of agreement in the views expressed. Our work has
been greatly assisted by the evidence received, which we have studied and taken
into account when reaching our conclusions, and we wish to record our thanks to
all those who contributed. Their names are listed in Appendix 1.
5. The Chairman and members of the Advisory Group would like to put on record
their appreciation of the help they have received from the Joint Secretaries,
Dr. Laycock and Mrs. S. E. Reeve. Throughout they have facilitated communica-
tion with the large number of people involved in the whole investigation, and
made an invaluable contribution to the repeated draftings that became necessary.
Without their help the enquiry would have been a much more difficult task.
19-1
MEDICAL BACKGROUND
Definitions
6. The ethical problems which have arisen in recent years in relation to organ
transplantation have emphasized the difficulties of defining terms as "life"
and "death." These difficulties have been encountered in the context of deci-
sions relating to adults and children but in the case of the fetus in mid-
pregnancy an additional difficulty arises in defining viability. In 1950 an
Expert Committee of the World Health Organization attempted to meet the problem
of definition but since that time advances in medical knowledge have made their
definitions unsatisfactory. We have decided to introduce our own definitions
of some of the more important terms used in this report, as we consider these
to reflect more accurately the current state of medical knowledge. Our defini-
tions are set out below:
The Fetus : the human embryo from conception to delivery (and therefore
including what is normally termed the embryonic state) .
A Viable Fetus: one which has reached the stage of maintaining the
coordinated operation of its component parts so that it is capable of
functioning as a self-sustaining whole independently of any connection
with the mother.
A Pre-Viable Fetus: one which, although it may show some but not all
signs of life, has not yet reached the stage at which it is able, and
is incapable of being made able, to function as a self-sustaining whole
independently of any connection with the mother.
Fetal Death: the state in which the fetus shows none of the signs of
life and is incapable of being made to function as a self-sustaining
whole.
Fetal Tissue: a part or organ of the fetus, e.g., the lungs or liver.
Fetal Material: any or all of the contents of the uterus resulting from
pregnancy excluding the fetus, i.e., placenta, fluids and membranes.
Research Involving the Use of the Dead Fetus and Fetal Material
7. Evidence was sought from a number of organizations known to use dead fetuses,
fetal tissues and fetal material in the course of their work. Our enquiries
showed that in most instances fetal tissues are used since tissues and cells
may continue to live for a period after the fetus itself has died, even if they
are separated from it. The use of the fetus as a whole is necessary only in a
small number of investigations at present.
19-2
8. Fetal tissues may be used in various valuable ways, particularly in preven-
tive medicine where there is generally no practical substitute for the fetal tis-
sues used. This is especially the case in the field of virology. The enquiries
we made showed that it is often difficult to distinguish between research uses
and the diagnostic or therapeutic uses of the work which is being done. Some
examples are described below and fuller details are given in Appendix 2.
9. Virology: Fetal tissues are used in the routine diagnosis of and research
on viruses pathogenic to man, notably those affecting the respiratory tract;
the largest present user for this purpose is the Public Health Laboratory Ser-
vice. Identification of different strains of the rhino viruses (the most com-
mon causes of colds) has been made possible on a large scale only by using
cultures obtained from fetal tissues since most of these organisms do not grow
on cultures of non-human cells.
10. The properties of both established and new vaccines against viral infections
are investigated in fetal tissue cultures, as these tissues provide excellent
purity tests for the vaccines. For example, work is in progress on an influenza
vaccine, and the vaccines for poliomyelitis and rubella (German measles) are
manufactured from fetal tissue. Thus the use of fetal tissues has gone beyond
basic research into the field of established practice in preventive medicine.
For the future, it seems probable that the use of fetal tissues will offer the
only chance for growing the viruses thought to cause hepatitis and infantile
gastroenteritis .
11. Cancer Research: Fetal tissues provide the best source of human cells that
can be kept growing in tissue culture for the study of induction of disordered
growth (analogous to cancerous growth) and of the effect of various agents on
that disordered growth. Research in this field opens up future possibilities
of diagnosis and treatment of cancer in children and adults.
12. Arterial Degenerative Disease: Fetal tissue cultures provide material for
research on the development of connective tissues in the arterial wall and so
may contribute to the knowledge of the origins of arterial degenerative disease.
13. Immunology: Fetal thymus cells and bone marrow grafts are used in research
into the treatment of certain diseases of infants where the normal mechanism for
resistance against infection is deficient (immuno-deficient conditions) . Fetal
cells are used to investigate renal and liver transplant rejection phenomena in
adults and for tissue typing in transplant surgery.
14. Congenital Deformities: Research on the whole dead fetus is essential for
the advancement of knowledge of fetal development and to investigate factors
that might interfere with this so as to produce congenital deformities. It has
already been found that the infection of the fetus with rubella virus can cause
congenital heart disease, blindness and deafness, and that certain drugs can
cause deformities of the limbs or internal organs; but many other structural
deformities remain to be investigated.
19-3
Research on the Fetus in Utero
15. Observations have been made on the fetus in utero to estimate its growth
especially that of the head, to study its responses to sensory stimuli and to
investigate the changes in heart rate. Special attention has been given to the
variations in blood composition during labour and to the circulatory and respi-
ratory changes which occur during and after birth.
Research on the Whole Pre-Viable Fetus
16. Research involving the whole pre-viable fetus has been carried out after
delivery in certain countries to increase knowledge of perinatal physiology
and pathology especially in regard to steroid metabolism. Stringent precautions
have been taken to ensure that the fetuses used for such investigations are not
viable.
Supply of Fetuses, Fetal Tissue and Fetal Material
17. Since 1958 the Medical Research Council has provided a grant to support the
collection, preservation and distribution of fetuses, fetal tissues and fetal
material by the Royal Marsden Hospital, London. About 40 different establish-
ments and individuals are supplied by this source. Inevitably costs for storage
and transport are incurred and where appropriate these are met by the recipient.
Outside the London area those requiring fetal tissues or material make similar
arrangements with local hospitals.
THE PRESENT LEGAL BACKGROUND
18. The law governing the issues under discussion falls naturally into four
parts: the criminal, the civil, the administrative (the statutes governing
registration of births and deaths etc.) and the disciplinary. In relation to
both the criminal and civil law it is pertinent to note that the research under
consideration is carried out in three separate legal jurisdictions (England and
Wales, Scotland and Northern Ireland) in which the machinery of law enforcement
is wholly, and the substantive law in part, different. An attempt to summarize
the law in more than broad outline could therefore lead to confusion and no
attempt is made to do so.
19. It is an important aspect of the law in all three jurisdictions that estab-
lished practices over the whole range of medical and nursing treatment in the
obstetric and paediatric field from the moment of conception until the fetus is
firmly established as a live or dead child (in the normal colloquial sense) are
subject to the strongest presumptions of legality.
19-4
Criminal Law
20. The purpose behind the criminal law has always been the protection of the
fetus at all stages. However, the law was developed and expounded before the
great changes brought about by scientific advances and by the passing of the
Abortion Act, with the result that the available authoritative statements of
the law do not provide clear guidance in the present situation. Development of
the law has also been limited by the rarity of cases in which the activities of
the medical profession have given rise to prosecution.
21. The problem is essentially new and if, as we think, a measure of control
is called for by both medical and lay opinion, the limited operation of the
criminal law makes it an inadequate guide or instrument for this purpose.
Having thus stated the limitations of criminal law, we have summarized what we
understand to be its general effect. In all three jurisdictions the following
acts may be taken to be criminal :
(a) deliberate or reckless injury to the fetus at any time between con-
ception and delivery save under the provisions of the Abortion Act. (In
this connection it is worth observing that the protection afforded to the
fetus is continuous and is not abrogated by the fact that it may be the
intention at the time of the infliction of the injury that the fetus
should be prevented by a subsequent abortion from attaining life.)
(b) deliberate or reckless injury to the fetus which has become a child
born alive or capable of being born alive. (In England and Wales and
Northern Ireland there is a statutory presumption that a fetus of 28
weeks development is capable of being born alive.)
Civil Law
22. Civil law requires of a medical practitioner who undertakes the treatment
of a patient the exercise of reasonable skill and care and treats failure in
such care as negligence. Any negligence in diagnosis or treatment (whether
experimental or not) which causes injury to a fetus will found a claim for
damages notwithstanding that the conduct of the practitioner has been neither
criminal nor unethical. Such a claim could also arise from harm caused to a
fetus following negligent certification that it was not viable.
Administrative Law
23. The administrative law may be briefly summarised. In all three jurisdic-
tions there are broadly similar statutory requirements for the registration of
births, deaths and still-births, and for notification of births to the public
health authority. These statutes have several purposes, statistical, adminis-
trative and protective of life. For present purposes only the last is relevant.
The requirement to register a birth applies only to live-births (irrespective
of the duration of pregnancy) and to still-births, i.e., births not being live-
births which take place after the 28th week of pregnancy. The delivery of a
dead fetus before that stage is not registrable, nor is it notifiable to the
public health authority.
Disciplinary Law
24. Much more material to the present problem is the disciplinary jurisdiction
of the Disciplinary Committee of the General Medical Council and, on appeal,
the Judicial Committee of the Privy Council. The Disciplinary Committee are
empowered by statute to erase a doctor's name from the register of medical prac-
titioners or to suspend his registration if they are satisfied that his behavior
constitutes "serious professional misconduct." They may also admonish a doctor
on the same grounds. The limits of serious professional misconduct may extend
far beyond those of criminal law. They reflect the high standard of ethical
behavior demanded of and accepted by the medical profession. The Disciplinary
Committee see their primary duty as protection of the public. Their proceedings
are public and their decisions are pxiblicly reported.
THE IMPLICATIONS OF RESEARCH ON FETUSES AND
FETAL MATERIAL
25. During our discussions we have been constantly aware of the public concern
and of the ethical problems surrounding the use of fetuses, fetal tissues and
fetal material for research. In reaching our conclusions, we have tried to
maintain a balance between them and the contribution to medical science made by
this form of research. In general, we feel that the contribution to the health
and welfare of the entire population is of such importance that the development
of research of this kind should continue subject to adequate and clearly defined
safeguards. In the following paragraphs we consider the implications of under-
taking research using the fetus, fetal tissue or fetal material and indicate the
safeguards which we consider essential in the interests of both the public and
the medical profession.
Research on the Fetus in Utero
26. We have given careful consideration to the question of carrying out research
involving the fetus during pregnancy. Investigations and tests may be carried
out with the intention of benefiting the mother, her expected child or both,
and in each instance ethical or legal objections do not arise. We understand
that suggestions have been made if it is the intention to terminate the preg-
nancy with the idea of preventing a live-birth, then it would be permissible
to administer substances to the mother in order to see if these are harmful
to the fetus. We cannot accept this. In our view it is unethical for a
19-6
medical practitioner to administer drugs or carry out any procedures on the
mother with the deliberate intent of ascertaining the harm that these might
do to the fetus, notwithstanding that arrangements may have been made to
terminate the pregnancy and even if the mother is willing to give her consent
to such an experiment.
27. Apart from these ethical considerations such experiments are undertaken at
the risk of the investigator since, if the fetus is alive on termination of
pregnancy but is handicapped or subsequently dies as a result of experiments
conducted during pregnancy, the persons concerned would be liable to prosecution.
Also, if the fetus is born alive but is handicapped as a result of such experi-
ments it would be open to the parent to seek compensation through the courts.
The existence of arrangements to terminate the pregnancy made before the experi-
ments are conducted would not necessarily constitute a valid defence.
Research on the Viable Fetus
28. We consider it is important that there should be no ambiguity about the
circumstances in which research can be carried out on a viable fetus. In our
view when the fetus is viable after delivery the ethical obligation is to sus-
tain its life so far as possible and it is both unethical and illegal to carry
out any experiments on it which are inconsistent with treatment necessary to
promote its life, although in many instances the techniques used to aid a dis-
tressed fetus are so new that they are in some degree experimental.
29. In England and Wales evidence of pregnancy for a period of 28 weeks or
more is accepted as prima facie proof that the mother is at that time pregnant
of a child capable of being born alive (Infant Life [Preservation] Act 1929) .
However in our view advances in medical knowledge have made it no longer accept-
able to take the 28th week of pregnancy as indicating the time at which a fetus
becomes capable of survival as fetuses delivered before that date, may, by modem
techniques, be enabled to live.
30. We noted that in April 1970 the International Federation of Obstetrics and
Gynaecology said that advances in neonatology had made parameters for definition
of the period of viability based on 28 weeks gestation age unrealistic. It
recommended that the term "abortion" which implied that life could not be main-
tained in the fetus after expulsion from the mother should be restricted to
terminations under 20 weeks (140 days) . Similar views were expressed by a num-
ber of the organizations who submitted written evidence to us including the
Royal College of Obstetricians and Gynaecologists and the Royal College of
Midwives, although recommendations on the period of gestation which should be
taken as prima facie evidence of viability varied from 18 to 24 weeks.
31. For ethical, medical and social reasons we recommend that for human fetuses
evidence of a period of gestation of 20 weeks (140 days: this corresponds to a
weight of approximately 400-500 grammes) should be regarded as prima facie proof
of viability at the present time. This date should be reviewed regularly to
19-7
take account of the rapid changes taking place in medical knowledge. Accordingly
consideration should be given to amendment of the Acts providing for registration
and notification of births and deaths, the Infant Life (Preservation) Act 1929
and analogous legislation in Scotland and Northern Ireland.
Research on the Pre-Viable Fetus
32. We have given long and careful consideration to the position of a fetus
which, although it shows signs of life in some of its organs, is pre-viable in
that it is incapable of attaining a state in which it could exist as a self-
sustaining whole independently of the mother. In our view, if it has been
shown that a missing vital function in a fetus cannot be established, for exam-
ple that the lungs are solid and therefore cannot be inflated, then the fetus
has not developed to the stage of being recoverable.
33. We have had to weigh the benefits of research involving pre-viable fetuses
against the objections which may be generated and the reasoned ethical and soc-
ial arguments which are involved. In considering whether it is ethically jus-
tifiable to undertake such research we noted that society through Parliament,
in permitting abortion in certain circumstances has accepted that where an abor-
tion under the Act is carried out the pre-viable fetus is prevented from attain-
ing life. Given this situation we have considered whether through research on
such fetuses new knowledge may be gained which would ultimately benefit viable
infants.
34. The medical evidence we received showed that the whole pre-viable fetus
has offered an important opportunity that cannot be obtained in any other way
for making observations of great value on the transfer of substances across the
human placenta, the reaction of the immature fetus to drugs, and on the endocri-
nological development of the placenta. There is a particular need to determine
the ability or otherwise of the fetus to deal with substances including drugs
given therapeutically to benefit the mother, which may cross the placenta.
Observations on the pre-viable fetus are necessarily limited to a period of two
or three hours. They have, however, already contributed significantly to our
understanding of vital physiological and biochemical processes before birth on
which the development of a fetus into a normal child essentially depends. As
yet our knowledge is not sufficient to enable us either to control or compensate
for any deviation from the normal in such processes. Research on the previable
fetus promises, however, to be the most hopeful approach to understanding certain
failures of the human brain to develop properly and the influence such factors
as variants in sexual differentiation in utero may have on inherent behavioural
patterns after birth.
35. We accept that in the case of single births any fetus of less than 20 weeks
gestational age (400-500 grammes) is pre-viable and as such has not yet reached
the stage at which it can exist as a living entity. We noted the evidence that
in the pre-viable fetus of 300 grammes or less as distinct from the fetus
approaching full term those parts of the brain on which consciousness depends
19-8
are, as yet, very poorly developed structurally and show no signs of electrical
activity. After exhaustive consideration we have reached a unanimous view that
it would be wrong to exclude the use of the pre-viable fetus for research, pro-
vided the following conditions are observed:
(1) Only fetuses weighing less than 300 graimties should be used.
(2) The responsibility for deciding that the fetus is in a category which
may be used for this type of research must rest with the medical atten-
dants at its birth and never with the intending research worker.
(3) Such research should only be carried out in departments directly
related to a hospital and with the direct sanction of the ethical com-
mittee to which reference is made later in this report (paragraph 47) .
(4) Before permitting such research the ethical committee should satisfy
itself: (a) on the validity of the research; (b) that the required infor-
mation cannot be obtained in any other way; and (c) that the investiga-
tors have the necessary facilities and skill.
Research on the Dead Fetus
36. When considering the implications of research on the whole dead fetus the
difference in the Acts governing the use of human tissue for research makes it
necessary to distinguish between the fetus which dies after birth and the fetus
which is dead because separation from the mother involves the termination of its
life.
37. Where a fetus dies after birth the provisions of the Anatomy Acts 1832 and
1871 and the Human Tissue Act 1961 apply as they would to any other deceased
person. Subject to the proper implementation of these provisions there are no
legal restrictions on the use of the whole fetus or parts thereof for research.
Where a fetus is born dead the Anatomy Act and the Human Tissue Act do not apply
and consequently there are no statutory restrictions on the use of the whole
fetus or parts thereof for research.
38. After a thorough examination of the evidence, we are satisfied that the
benefits to be derived from the use of the whole dead fetus in the prevention
and treatment of disease and deformity are such that it would be a retrogres-
sive step to prevent it. In our view it should be allowed to continue, pro-
vided it is carried out within the context of the general recommendations which
we made later in this report on the control to be exercised whenever fetuses,
fetal tissues or fetal material are used for research.
Research on Fetal Tissues and Fetal Material Other Than the Fetus
39. Having regard to the essential contribution that is made by this research
to preventive medicine there is, in our view, no reason to object to the use of
fetal tissues and fetal material for these purposes subject to our general
recommendations for control over research referred to later in the report.
40. Since 1958 commercial use of the placenta and retroplacental blood, not
otherwise used by the National Health Service, has been accepted practice pro-
vided that the products to be derived from them are intended for therapeutic use.
We see no ethical or legal objections to this practice.
Consent to Research
41. Where a fetus is viable the overriding responsibility of the doctor is to
promote and preserve its life and the parent's consent can normally be inferred
for procedures consistent with this aim. There are also areas of research which
whilst not jeopardising the health and welfare of the fetus are not of direct
benefit to that particular fetus. In such cases we consider that express consent
should be obtained from the parent. As stated in paragraph 37, where the fetus
is born alive and later dies the provisions of the Human Tissue Act and the Acts
concerned with certification of causes of death and investigation by coroners
(in Scotland, Procurators Fiscal and Sheriffs) apply and enquiry must be made as
to whether there is no objection on the part of the parent before the body can
be used for research.
42. Where the separation of the fetus from the mother leads to the termination
of its life there is no statutory requirement to obtain the parent's consent for
research, but equally there is no statutory power to ignore the parent's wishes.
A number of organizations who discussed this question in their evidence expressed
the view that to seek consent could be an unnecessary source of distress to par-
ents. We share this view but believe the parent must be offered the opportunity
to declare any special directions about the disposal of the fetus. In our view
this opportunity could be provided by adding an appropriate clause to the form
giving the patient's consent to the operation thus minimising any possible
distress .
Conscientious Objections
43. The evidence we received strongly suggested that some members of staff may
have conscientious objections to the use of fetuses or fetal tissues for research.
We recommend that no member of staff should be under any duty to participate in
research on the fetus, fetal tissue or fetal material if he or she has a con-
scientious objection. We also received representations that experiments on the
fetus or dissections for fetal tissues should not be carried out within the oper-
ating theatre or place of delivery. We have no reason to believe that this has
ever occurred, but we agree that it should not happen.
19-10
44. The public disquiet voiced about the use of fetuses, fetal tissue and fetal
material for research has been influenced in part by the suggestion that finan-
cial transactions are involved. In our view any charges made are acceptable only
if they do no more than meet the necessary costs incurred in administering these
services, such as those provided by the Royal Marsden Hospital. In no other cir-
cumstances should there be monetary exchange for fetuses, fetal tissue or fetal
material.
Record of Fetuses, Fetal Tissue and Fetal Material
45. We recommend that wherever fetuses, fetal tissue or fetal material are used
for research the relevant institutions should ensure that a record is kept of all
such material supplied or received and of its source and destination. In our
view this record would be a valuable safeguard and should be available to central
advisory body to which we refer later in the report.
FUTURE CONTROL OF RESEARCH
46. Because of the concern expressed generally over this form of research we
have given particular attention to its future control. We note that a report
published in 1967 by the Committee on the Supervision of the Ethics of Clinical
Investigations in Institutions set up by the Royal College of Physicians of Lon-
don recommended that:
"The competent authority (e.g.. Board of Governors, Medical Schools
Council, Hospital Management Committee, or equivalent body in non-
medical institutions) has a responsibility to ensure that all clinical
investigations carried out within its hospital or institution are
ethical and conducted with the optimum technical skill and precautions
for safety. This responsibility would be discharged if, in medical
institutions where clinical investigation is carried out, it were
ensured that all projects were approved by a group of doctors
including these experienced in clinical investigation. This group
should satisfy itself of the ethics of all proposed investigations.
In non-medical institutions or wherever clinical investigation (i.e.,
any form of experiment on man) is conducted by investigators with
qualifications other than medical the supervisory group should always
include at least one medically qualified person with experience in
clinical investigation."
This was accepted by the Ministry of Health and Hospital Memorandum (68) 33 asked
hospital authorities in England and Wales to arrange with the medical staff of
their hospitals for it to be put into effect.
19-11
47. We recommend that all research using the fetus, fetal tissue or fetal
material should be approved by such a committee whatever the institution in
which the research is undertaken; research involving the previable fetus should
only be carried out in departments directly related to hospitals. The commit-
tee should accept responsibility for ensuring that such investigations are
ethical. In approving research projects using the fetus, fetal tissue or fetal
material the committee should use as a guideline the principles which we set
out in the suggested Code of Practice at the end of this report.
48. We considered whether this type of research justified any safeguards addi-
tional to those mentioned already, in particular whether a lay member should be
appointed to the ethical committee. Our conclusion was that clinical decisions
are the responsibility of the clinician, and the ethical questions are for the
profession to consider. Given a change in the minimum limit of viability (see
paragraph 31), and guidance to the profession in a code of practice, together
with the overall safeguards of the law, particularly the disciplinary control
referred to in paragraph 24, we consider that the interests of all concerned
would be sufficiently protected.
49. Some of the evidence received suggested that there should be legislation
to provide for the licensing of those who wished to undertake research using
fetuses, fetal tissue or fetal material similar to the licenses issued to those
undertaking research on animals. In our view a system of licensing would be
unnecessarily cumbersome and a code of ethical practice would be an adequate
safeguard as it is in the case of research involving all patients. A code would
have the advantage of flexibility in that it could be modified in the light of
future experience without recourse to amending legislation, and it would not
entail the establishment of permanent machinery for the issue of licenses and
an inspectorate.
50. We also considered whether any central body should be set up to advise in
cases where the local committee is uncertain of the ethics of particular inves-
tigations. We concluded that it would not be necessary to have a permanent body
to handle the limited number of enquiries which are likely to rise. Instead we
recommend that arrangements should be made for a small informal advisory body
with legal representation and including members drawn from the Medical Research
Council, the Royal College of Obstetricians and Gynaecologists, the General Medi-
cal Council and the British Paediatric Association to be convened when the need
for central advice arises. It might be considered appropriate for this advisory
body to cover the United Kingdom.
19-12
RECOMMENDED CODE OF PRACTICE
This code has no binding legal force but is the result of a careful con-
sideration of all relevant factors in the light of the available evidence. It
is hoped that it will prove acceptable to the bodies statutorily responsible
for disciplinary matters in the medical and nursing professions.
1. Where a fetus is viable after separation from the mother it is unethi-
cal to carry out any experiments on it which are inconsistent with treatment
necessary to promote its life.
2. The minimal limit of viability for human fetuses should be regarded
as 20 weeks' gestational age. This corresponds to a weight of approximately
400-500 grammes.
3. The use of the whole dead fetus or tissues from dead fetuses for
medical research is permissible subject to the following conditions:
(i) The provisions of the Human Tissue Act are observed where
applicable;
(ii) Where the provisions of the Human Tissue Act do not apply
there is no known objection on the part of the parent who
has had an opportunity to declare any wishes about the dis-
posal of the fetus;
(iii) Dissection of the dead fetus or experiments on the fetus
or fetal material do not occur in the operating theatre
or place of delivery;
(iv) There is no monetary exchange for fetuses or fetal material;
(v) Full records are kept by the relevant institution.
4. The use of the whole previable fetus is permissible provided that:
(i) The conditions in paragraph 3 above are observed; - -■ • • ■ • ■ ..
(ii) Only fetuses weighing less than 300 grammes are used;
(iii) The responsibility for deciding that the fetus is in a cate- ■
gory which may be used for this type of research rests with ■ ■.• ;
the medical attendants at its birth and never with the
intending research worker; ■ --• ■
(iv) Such research is only carried out in departments directly ■■■
related to a hospital and with the direct sanction of its
ethical committee;
(v) Before permitting such research the ethical committee satis-
fies itself: (a) on the validity of the research; (b) that
the required information cannot be obtained in any other way;
and (c) that the investigators have the necessary facilities
and skill.
5. It is unethical to administer drugs or carry out any procedures during
pregnancy with the deliberate intent of ascertaining the harm that they might do
to the fetus.
19-13
APPENDIX 1
Organizations and Individuals Who Submitted Evidence to the Advisory Group
(i) The following organizations submitted evidence to the Group:
Blair Bell Research Society
Board for Social Responsibility of the National Assembly of the
Church of England
British Council of Churches
British Medical Association
British Paediatric Association
Karolinska Institute-Department of Obstetrics and Gynaecology (Stockholm)
Medical Research Council (evidence was also submitted by the Reproduction
and Growth Research Unit of the MRC)
Medical Women's Federation
National Association of Theatre Nurses
National Institute of Health, Bethesda, United States
Office of the Chief Rabbi
Patients Association
Public Health Laboratory Service
Roman Catholic Church .
Royal College of Midwives
Royal College of Nursing and National Council of Nurses in the United
Kingdom
Royal College of Obstetricians and Gynaecologists
Society for the Protection of Unborn Children
Swedish Committee on International Health Relations
Swedish Medical Research Council-Reproductive Endocrinology Unit
Union of Liberal and Progressive Synagogues
Universities of Aberdeen, Dundee and Edinburgh
(ii) The following individuals submitted evidence to the Group:
Mr. Michael Wilkinson, FRCS
Mr. R. Wilson, MSc
19-14
APPENDIX 2
Projects Utilizing Human Fetuses, Fetal Tissue and Fetal Material
The work reported has been loosely grouped into physiological and anatomical
categories. Items mentioned here include some of those already referred to
in the text.
General Fetal Metabolism
1. Fetal head measurements to confirm the accuracy of ultrasonic cephalometry .
2. Fetal size in relation to amniotic fluid production.
3. Fetal size in relation to maternal smoking habits in and before pregnancy.
4. Water exchange between maternal, fetal and amniotic fluid environments.
5. The changes in oxygen partial pressures and acid base balance in hypoxia at
various stages of pregnancy.
6. Carbohydrate metabolism in hypoxic fetuses and the effects of maternal dex-
trose infusions.
7. Glycoprotein synthesis in fetal liver.
8. Study of glucoronide metabolism for future treatment of neonatal jaundice
or steroid imbalance.
Endocrinology
1. Detection of hormones that are solely fetal in origin and could possibly
be measured in maternal tissues to enable the degree of fetal well-being
to be determined.
2. Adrenal steroid metabolism in the fetal gland and the excretion of such
steroids into the amniotic fluid at various stages.
3. Investigation of prolactin using fetal pituitary glands.
4. Cholesterol metabolism in relation to plasma protein levels.
5. Insulin secretion in the fetal pancreas and the effects on carbohydrate
metabolism.
6. Gonadotrophin assay in fetal pituitary glands and stimulation of fetal
pituitary activity in vitro.
7. Fetal intracellular binding site of progesterone with reference to possible
blocking of histocompatible antigens.
8. Parathyroid metabolism in early pregnancy.
Haematology
1. Blood volume studies at different maturities.
2. Changes in fetal blood composition and development of plasma proteins.
3. Bone marrow maturation in relation to peripheral fetal blood.
4. Folate metabolism in the fetus and its accumulation in various tissues —
notably liver and pancreas .
19-15
5. Studies of rhesus incompatibility using fresh suspensions of fetal liver
cells .
6. Structure and properties of fetal haemoglobin and its variants.
Cardiology
Fetal electrocardiography performed directly on hysterotomy specimens and
correlation with records made whilst the fetus was in utero.
Alimentary Tract
1. Fetal swallowing mechanisms in mid-trimester and the effects of anencephaly.
2. The pharmacology and innervation of small gut of the fetus.
3. The activity of some liver enzymes and their alteration with maturity.
4. Vitamin A content and activity of liver (and brain) .
Renal and Urinary Tracts
1. Urine excretion and the production of amniotic fluid.
2. Changes in constitution of fetal urine in relation to renal maturity.
3. Culture of renal tissues to elucidate the development of fetal renal
malignancies.
Skin
1. The origin and shedding of skin cells into the liquor.
2. Permeability of fetal skin and its variations with maturity.
3. The growth of fetal oral squamous epithelium in tissue culture.
4. Steroid metabolism in various skin sites of the body.
5. Biochemical assay of glycogen in fetal skin as a means of glycogen storage.
Amniotic Fluid Physiology
1. The circulation of fluid in relation to fetal and placental weight.
2. Composition of fluid in relation to fetal blood.
3. The origin and development of cells in the amniotic fluid.
4. Electrical conductivity of fluid and its effects in fetal electrocardio-
graphic studies.
5. Secretion of steroid hormones from the vessels of the umbilical cord into
the liquor.
6. Alterations in trace metal metabolism in relation to proteins and electro-
lytes levels in amniotic fluid.
19-16
Placental Metabolism
Much work is proceeding in the transfer of various drugs and macromolecules ,
while other research is investigating glucose, amino-acid and steroid trans-
fers .
Immunology
1. Fetal antibody production in hosts of other species with subcellular
fractions from hemogenates of the fetal tissues.
2. Carcinoma embryonic antigens present in adult tumours and fetal tissue
only. Developments in their use in diagnosis of cancer in the adult
and possibly their use for cancer therapy.
3. Fetal thymus cells are used in the investigation of human antilymphocyte
globulin and other immunosuppressive agents.
4. Research on auto-immune conditions and immunopathological states using
fetal tissue.
Chromosome Studies
1. Abnormalities in therapeutic abortions (providing background figures to
those produced after spontaneous abortions) .
2. Y chromosome detection by fluorescent techniques.
3. Effect of X irradiation on chromosomes in ovarian tissue culture and
total numbers of ova.
Anatomy
1. Fetuses are used at all stages of development for teaching of medical and
nursing students.
2. Studies of neuro-anatomy using fetal brain tissue.
Printed in England for Her Majesty's Stationery Office
by Ebenezer Baylis & Son Ltd., The Trinity Press, Worcester, and London
19-17
20
PROTECTION OF HUMAN SUBJECTS:
POLICIES AND PROCEDURES
Federal Register, November 16, 1973, DHEW
01
0
-8
FRIDAY, NOVEMBER 16, 1973
WASHINGTON, D.C.
Volume 38 ■ Number 221
PART II
DEPARTMENT OF
HEALTH,
EDUCATION,
AND WELFARE
■
NATIONAL INSTITUTES
OF HEALTH
Protection of Human Subjects
Policies and Procedures
No. aai— pt. II — 1
NOTICES
DEPARTMENT OF HEALTH.
EDUCATION, AND WELFARE
National Institutes of Health
PROTECTION OF HUMAN SUBJECTS
Policies and Procedures
In the Federal Register of October 9.
1973 (38 FR 27882 et seq). the Secre-
tary of Health, Education, and Welfare
issued a notice of proposed rulemaking
concerning the protection of human sub-
jects and mentioned that DHEW through
the National Institutes of Health, had
appointed a special study group to re-
view and recommend policies and special
procedures for the protection of chil-
dren, prisoners, and the institutionalized
mentally infirm in research, develop-
ment, and demonstration activities. The
report of this study group has been com-
pleted in drajt form and reviewed by the
Director, NIH.
There may well be elements in the
recommendations which will provoke
debate and controversy. We recognize
that public consideration and comment
are vital to the development of our final
recommendations to the Secretary' and
are inviting such comment now even
though the materials are still pending
final review and completion. The product
of our effort after considering public
comment will be transmitted to the As-
sistant Secretary for Health. HEW to
recommend to the Secretaiy, HEW that
it appear again in the Federal Register
as proposed rulemaking for further pub-
lic comment. Such a procedure is con-
sistent with long established DHEW pol-
icy for permittmg extensive public op-
portunity to affect the promulgation of
DHEW regulations.
It must be clearly understood by the
reader that the material that follows is
not proposed rulemaking in the technical
sense, and is not presented as Depart-
mental. Public Health Service, or NIH
policy. Rather it is a draft working docu-
ment on which early public comment
and participation is invited.
Please address any comments on these
draft policies and procedures to the Di-
rector. National Institutes of Health. 9000
Rockville Pike, Bethesda. Maryland
20014. All comments should be received
by January 4, 1974.
Additional copies of this notice are
available from the Chief. Institutional
Relations Branch, Division of Research
Grants. National Institutes of Health,
9000 Rockville Pike, Bethesda. Maryland
20014.
Dated: Novembers. 1973.
Robert S. Stone,
Director,
National Institutes of Health.
Research. Development, and Demonstra-
tion Activities: Limitations of In-
formed Consent
special policy considerations
SutmTiary
November 5. 1973.
The mission of the Department of
Health. Education, and Welfare Includes
the improvement of the health of the Na-
tion's people through research, develop-
ment, and demonstration activities which
at times involve human subjects. Thus,
policies and procedures are required for
the protection of subjects on whose par-
ticipation these activities depend.
Informed consent is the keystone of
the protection of human subjects in-
volved in research, development, and
demonstration activities. Certain cate-
gories of persons have limited capacity
to concent to their involvement in such
activities. Therefore, as a supplement to
DHEW policies, special protections are
proposed for children, prisoners, and the
mentally infirm, who are to be involved
in research, development, and demon-
stration activities.
Agency "Ethical Review Boards" are to
be established to provide rigorous review
of the ethical issues in research, develop-
ment, and demonstration activities in-
volving human subjects, in order to
make judgments regarding societal ac-
ceptability in relation to scientific value.
"Protection Committees" are to be estab-
lished by the applicant to provide "sup-
plementary judgment" concerning the
reasonableness and validity of the con-
sent given by, or on behalf of. subjects.
The intent of this policy is that institu-
tions which apply for DHEW funds or
submit research in fulfillment of DHEW
regulations, must be in compliance with
these special protections, whether or not.
particular research, development, or dem-
onstration activities are Federally acti"
ities.
1, Children. If the health of children is
to be improved, research activities in-
volving their participation is often essen-
tial. Limitation of their capacity to give
informed consent, however, requires that
certain protections be provided to assure
that scientific importance is weighed
against other social values in determining
acceptable risk to children. Therefore,
research, development, and demonstra-
tion activities which involve risk to chil-
dren who participate must:
a. Include a mechanism for obtaining
the consent of children who are 7 years
of age or older;
b. Include the applicant's proposal for
use of a Protection Committee which is
appropriate to the nature of the activity;
c. Be reviewed and approved, in con-
formity with present DHEW policy, by
an Organizational Review Committee;
and
d. Be reviewed by the appropriate
agency Primai-y Review Committee, the
Ethical Review Board, and tlie appro-
priate secondary review group.
2, Special categories. — a. The Abortus.
No research, development, or demonstra-
tion activity involving the non- viable
abortus shall be conducted which:
1. Will prolong heart beat and respira-
tion artificially solely for the purpose of
research ;
2 Will of itself terminate heart beat
and respiration:
3, Ha^ not been reviewed by the agency
Ethical Review Board: and
4 Has not been consented to by the
pregnant woman with participation of a
Protection Committee.
(An abortus having the capacity to sus-
tain heart beat and respiration is In fact
a premature infant, and all regulations
governing research on children apply.)
b. The fetus in utero. No research
Involving pregnant women shall be con-
ducted unless:
1. Primary Review Groups assure that
the activity is not hkely to harm the
fetus;
2. the agency Ethical Review Board
has reviewed the activity;
3. a Protection Committee is operat-
ing in a manner approved by the agency;
and
4. the consent of both prospective
legal parents has been obtained, when
reasonably possible.
c. Products of in vitro fertilization. No
research involving implantation of
human ova which have been fertilized
in vitro shall be approved until the
safety of the technique has been demon-
strated as far as possible in sub-human
primates, and the responsibilities of the
donor and recipient "parents" and of
research institutions and personnel have
been established. Therefore, no such re-
search may be conducted without review
of the Ethical Review Board and of a
Protection Committee.
3. Prisoners. Research, development,
and demonstration activities involving
human subjects often require the partic-
ipation of normal volunteers. Prisoners
may be especially suitable subjects for
such studies, although there are prob-
lems concerning the voluntariness of the
consent of normal volunteers who are
confined in institutions. Certain pro-
tections are required to compensate for
the diminished autonomy of prisoners in
giving voluntarj- consent. Research, de-
velopment, and demonstration activities
involving prisoners must:
a. Include the applicant's proposal for
use of a Protection Committee which is
appropriate to the nature of the activity:
b. Be reviewed and approved by an
Organizational Review Committee which
may already exist in compliance with
present DHEW policy or which must be
appointed in a manner approved by the
appropriate DHEW agency;
c. Be reviewed by the agency Primary
Review Committee; and
d. Be conducted m an institution
which is accredited by the Secretary of
Health. Education, and Welfare.
4. The mentally infirm. Insofar as the
institutionalized mentally infirm might
lack either the competency or the au-
tonomy tor both! to give informed con-
sent, their participation in research re-
quires additional protection:
a. Research, development and demon-
stration activities involving the mentally
infirm will be limited to investigations
concerning 1 1 > diagnosis, etiolog>*. pre-
vention, or treatment of the disability
from which they suffer, or (2i aspects of
institutional life, per se. or (3) infor-
mation which can be obtained only from
such subjects.
All research, development and demon-
stration activities involving such per-
sons must:
1. Include the applicant's assurance
that the study can be accomplished only
FEDERAL REGISTER, VOL. 38, NO 221 — FRIDAY, NOVEMBER 16.
NOTICES
31739
with the participation of the mentally
Inflrm;
2. Include the applicant's proposal
for use of a Protection Committee which
Is appropriate to the activity; and
3. Be reviewed and approved by an
Organizational Review Committee, in
conformity with present DHEW policy.
Table (
' Contents
Introduction.
I. Definitions,
II. General policy considerations.
III. Children,
A Policy considerations.
B Agency Ethical Review Board: Eth-
ical review of projects,
C. Protection Committee; Protection of
Individual subjects.
D. Special provisions.
E. The fetus.
IV. Special categories.
A. The abortus.
B. The products of in vitro fertlllza-
V. Prisoners
A, Policy considerations,
B, Organizational Review Committee.
C, Protection Committee.
D, Payment to prisoners,
E, Accreditation.
F, Special provisions.
VI. The mentally infirm
A. Policy considerations.
B. Ethical review of projects and pro-
tection of subjects,
VU. General provisions.
A. Referrals to the Ethical Review
Board.
B. Procedures requiring special consid-
eration ,
C. Research conducted In foreign coun-
tries.
D. Research submitted pursuant to
DHEW regulatory requirements.
E. Clinical research not funded by
DHEW.
F. Confidentiality of Information and
records.
Vni. Draft regulations.
Introduction
The mission of the Department of
Health, Education, and Welfare includes
the improvement of the health of the
Nation's people through biomedical re-
search. This mission requires the estab-
lishment of policy and procedures for the
protection of subjects on whose partici-
pation that research depends. In DHEW
policy, as well as In ethical codes per-
taining to research in human subjects,
the keystone of protection is informed
consent.
An uncoerced person of adult years
and sound mind may consent to the ap-
pUcation of standard medical procedures
In the case of illness, and when fully and
properly informed, may legally and
ethically consent to accept the risks of
participating in research activities. Par-
ents and legal guardians have authority
to consent on behalf of their child or
ward to established therapeutic proce-
dures when the child is suffering from an
Illness, even though the treatment might
involve some risk.
There is no firm legal basis, however,
for parental or guardian consent to par-
ticipation in research on behalf of sub-
jects who are incompetent, by virtue of
age or mental state, to understand the
information provided and to formulate
the judgments on which valid consent
must depend In addition, current poli-
cies for clinical research afford such sub-
jects inadequate protection. Nevertheless,
to proscribe research on all such subjects,
simply because existing protections are
inadequate, would be to deny them po-
tential benefits, and is, therefore, in-
equitable. Knowledge of some diseases
and therapies can be obtained only from
those subjects (such as children^ who
suffer from the disease or who will be
receiving the therapy. Their participa-
tion in research is necessary to progress
in those fields of medicine. When such
subjects participate in research, they
need more protection than is provided
by present policy.
There are other individuals who might
be able to comprehend the nature of the
research, but who are Involuntarily con-
fined in institutions. Insofar as incar-
ceration might diminish their freedom
of choice, and thus limit the degree to
which informed consent can be freely
given, they too need additional protec-
tion. Current policies do not recognize
the limitations on voluntariness of con-
sent which may emanate from incar-
ceration.
This addition to existing policy is of-
fered as a means of providing adequate
protection to subjects who, for one rea-
son or another, have a limited ability to
give truly informed and fully autono-
mous consent to participate in research.
The aim Is to set standards which are
both comprehensive and equitable, in
order to provide protection and. to the
extent consistent with such protection,
maintain an environment in which clin-
ical research may continue to thrive.
1. Definitions. For purposes of this
policy :
A. Subject at risk means any individ-
ual who might be exposed to the possi-
bility of harm (physical, psychological,
sociological, or other) as a consequence
of participation as a subject in any re-
search, development or demonstration
activity (hereinafter called "activity")
which goes beyond the application of es-
tablished and accepted methods neces-
sary to meet his needs.
B. Clinical research means an inves-
tigation involving the biological, behav-
ioral, or psychological study of a per-
son, his body or his surroundings. This
includes but is not limited to any medi-
cal or surgical procedure, any withdraw-
al or removal of body tissue or fluid, any
administration of a chemical substance,
any deviation from normal diet or daily
regimen, and any manipulation or ob-
seravtion of bodily processes, behavior
or environment. Clinical research com-
prises four categories of activity;
1. Studies which conform to estab-
lished and accepted medical practice
with respect to diagnosis or treatment of
an illness.
2. Studies which represent a deviation
from accepted practice, but which are
specifically aimed at improved diagnosis,
prevention, or treatment of a specific ill-
ness In a patient.
3. Studies which are related to a pa-
tient's disease but from which he or she
will not necessarily receive any direct
benefit.
4. Investigative, non- therapeutic re-
search in which there is no intent or ex-
pectation of treating an illness from
which the patient Is suffering, or In
which the subject is a "normal control"
who is not suffering from an Illness but
who volunteers to participate for the po-
tential benefit of others.
It is important to emphasize that
"non-therapeutic" is not to be under-
stood as meaning "harmful." Under-
standing of normal processes Is essen-
tial; it is the prerequisite, in many in-
stances, to recognition of those devia-
tions from normal which define disease.
Important knowledge can be gained
through such studies of normal proc-
esses. Although such research might not
in any way benefit the subjects from
whom the data are obtained, neither
does it necessarily harm them.
Patients participating in studies iden-
tified in paragraph B-1, above, are not
considered to be at special risk by virtue
of participating in research activities,
and this policy statement offers no spe-
cial protection to them. When patients
or subjects are involved in procedures
identified in paragraphs B2. B3, and B4,
they are considered to be "at risk." and
the special policy and procedures set
forth in this document pertain. Excluded
from this definition are studies in which
the risk is negligible, such as research re-
quiring only, for example, the recording
of height and weight, collecting excreta,
or analysing hair, deciduous teeth, or nail
clippings. Some studies which appear to
involve negligible physical risk might,
however, have psychological, sociological
or legal implications which are signifi-
cant. In that event, the subjects are in
fact "at risk," and appropriate proce-
dures described in this document shall
be applied.
C. Children are Individuals who have
not attained the legal age of consent to
participate in research as determined
imder the applicable law of the jurisdic-
tion in which the proposed research is to
be conducted.
D. Pregnancy encompasses the period
of time from implantation until delivery.
All women during the child bearing years
should be considered at risk of preg-
nancy; hence, prudence requires defini-
tive exclusion of pregnancy when women
in this period of life are subjects for ex-
perimentation which might affect the
fetus.
E. Fetus means the product of concep-
tion from the time of implantation to
the time of delivery from the uterus.
P. Abortus means a fetus when it is
expelled whole, whether spontaneously
or as a result of medical or surgical inter-
vention undertaken with the intention
of terminating a pregnancy, prior to
viability. This definition, for the purpose
of this policy, excludes the placenta, fetal
material which Is macerated at the time
of explusion, a dead fetus, and Isolated
FEDERAL REGISTER, VOL 38, NO. 221 — FRIDAY, NOVEMBER U, 1973
31740
fetal tissue or organs excised from a dead
fetus.
G. Vlabtlity 0/ the letus, means the
ability of the fetus, after either a spon-
taneous delivery or an abortion, to sur-
vive to the point of Independently main-
taining vital functions: such a "viable"
fetus Is a premature Infant. Determina-
tion of viability entails a subjective and
objective Judgment by the physician at-
tending labor or examining the product
of conception, and must be made by a
physician other than the Investigator
wishing to use fetal tissue in research. In
general, and all other circumstances not-
withstanding, a beating heart is not suffi-
cient evidence of viability. At least one
additional necessary condition is the
possibility that the lungs can be Inflated.
Without this precondition, no currently
available mechanisms to initiate or main-
tain respiration can sustain life; and in
tWs case, though the heart is beating, the
fetus or abortus is in fact non-viable.
H. In vitro fertilization is any fertili-
zation of human ova which occurs out-
side the body of the female, either
through admixture of donor spei-m and
ova or by any other means.
I. Prisoner is any individual involun-
tarily confined in a penal institution.
The term in intended to encompass indi-
viduals sentenced to such an institution
under a criminal or civil statute, or Indi-
viduals detained by virtue of statutes
which provide alternatives to criminal
prosecution.
J. Mentally infirm includes the men-
tally ill, the mentally i-etarded, the emo-
tionally disturbed, the p.sychotlc, the
senile, and others mth impairments of
a similar nature, residing as patients In
an institution, regardless of whether or
not the Individual has been determined
to be legally incompetent,
K. Informed consent has two elements:
comprehension of adequate information
and autonomy of con.sent. Consent is a
continuinak process. The person giving
consent must be informed fully of the
nature and purpose of the research and
of the procedures to be used, including
Identification of those procedures which
are experimental, the possible attendant
short or long term risks and discom-
forts, the anticipated benefits to himself
and/or others, any alternative methods
of treatment, expected dm-atlon of the
study, and of his or her freedom to ask
any questions and to withdraw at any
time, should the person wish to do so.
There must also be written evidence of
the process used for obtaining informed
consent, including grounds for belief
that the subject has understood the in-
formation given and has sufficient ma-
turity and mental capacity to make such
choices and formulate the requisite judg-
ment to consent. In addition, the per-
son must have sufficient autonomy to
choose, without duress, whether or not
to participate. Both the comprehension
of Information and the autonomy of con-
sent are necessary elements: to the ex-
tent that either of these is in doubt, the
adequacy of Informed consent may be in
doubt.
NOTICES
L. Supplementary iudgment Is the
Judgment made by others to assent, or to
refuse to assent, to procedures for which
the subject cannot give adequate con-
sent on his or her own behalf. For the
purposes of this document, supplemen-
tary Judgment will refer to Judgments
made by local committees in addition to
the subject's consent 'when possible'
and that of the parents or legal cuardlan
'where applicable) , as to whether or not
a subject may participate in clinical re-
search. This supplementary Judgment Is
to be confirmed by the signature of the
Chairman of the Protection Committee
on the consent form. In accordance with
the procedures approved by the agency
for the Protection Committee, the Chair-
man's signature may be affixed on a
standard consent form, or may need to
be withheld until the Committee ap-
proves the participation of the Individual
subject.
II. General policy considerations. In
general, clinical research, like medical
practice, entails some risk to the sub-
jects. When the potential subject is un-
able fully to comprehend the risks which
might be Involved, or to make the Judg-
ment essential to consent regarding the
assumption of those risks, current guide-
lines suggest obtaining the consent of the
parents or legal representative.
Whereas it is clear by law that con-
sent of a parent or legal representative
is valid for established and generally ac-
cepted therapeutic procedmes performed
on a child or an incompetent adult, it is
far from clear that it is adequate for re-
search procedures. In practice, parental
or guardian consent generally has been
accepted as adequate for therapeutic re-
search, although the issue has not been
definitively resolved in the courts. When
research might expose a subject to risk
without defined therapeutic benefit or
other positive effect on that subject's
well-being, parental or guardian consent
appears to be insufficient.
In the case of prisoners, confinement
Imposes limitations on freedom of choice
which brings into question their ability
to give voluntary consent. A prisoner's
ability to give consent may be restricted
by overt or potential coercion, or by the
lass of personal autonomy generally con-
sidered to result from Incarceration it-
self. Therefore, additional protection
must be afforded this group even though
an individual's competency to under-
stand what is Involved might not be in
doubt.
The institutionalized mentally infirm
are doubly limited: as with children,
they might not be competent to make
informed judgments, and, as with pris-
oners, they are confined under condi-
tions which limit their civil freedom and
autonomy. Therefore, their participation
in research requires special protections.
The law is not clear on these issues.
Even if the law were clear, however, ethi-
cal questions would remain; specifically,
whether, and under what conditions re-
search involving these subject groups
may proceed. Resolution of these ethical
questions requires Judgments concerning
both the ethics of conducting a particular
research project, and the adequacy of
procedures for protecting the individual
subjects who will be asked to participate.
The intention of this policy Is to broaden
the scope of review, preclude or resolve
conflicts of Interest, and Invoke social as
well as scientific Judgments to protect
potential subjects who might have
dimlmshed cajiaclty to consent.
The proposed mechanism for protect-
ing subjects with limited ability to give
informed consent culminates in a form of
supplementary Judgment, which Is to be
supportive and protective of the sub-
ject's best Interests and wishes, to the
extent that he or she Is capable of for-
mulating and expressing a Judgment. In
the case of children and the mentally
Infirm, it will supplement their Judgment
and that of their parents or guardians.
In the case of competent individuals who
have restricted autonomy, it will support
and protect their wishes. Through this
mechanism, these subjects will be pro-
tected as fiilly as possible by community
review: however, the nature of some re-
search procedures might be such that, in
addition, court review ultimately will be
required.
III. Participation of children in re-
search— A. Policy considerations. Chil-
dren have generally been considered In-
appropriate subjects for many research
activities because of their inability to
give informed consent. There are circum-
stances, however, which not only justify,
but even require their participation. Chil-
dren do differ from adults in their
physiologic responses, both to drugs and
to disease: if the health of children is
to be improved, it is necessary to know
the nature and extent of these differ-
ences, and to have a full understanding
of normal patterns of growth and devel-
opment, metabolism, and biochemistry in
the pennatal. infant, early childhood,
pubertal and adolescent stages of devel-
opment. Studies of normal physiology
and behavior can also provide significant
benefit to children suffering from disease:
children are the only subjects from whom
these data can be obtained. Further-
more, there are diseases which cannot
be induced in laboratory animals, and
occur only rarely, if at all. in human
adults. In such cases, children are the
only subjects in whom the disease proc-
ess and possible modes of therapy can
be studied.
The Kefauver-Harris Act' requires
that drugs be tested for safety, efficacy
and dosage in children and pregnant
women before being approved for use to
treat illness in such patients. Food and
Drug Administration (FDA) approval
for the use of a new drug depends
upon submission of proposed label-
ing for a new drug, which must
include "adequate directions for use"
and "adequate warnings" as to unap-
proved uses." Acceptance of a new drug
' Federal Food, Drug, and Cosmetic Act.
1962 (FDC Act). 21 U.S.C. Sec. 301 et. seq.
•FDC Act Sec. 502(t). 21 U.S.C. Sec. 3S2(f).
FEDERAt REGISTER. VOL. 36, NO. J21— FRIDAY, NOVEMBER 16. l'>73
NOTICES
31741
rests on the adequacy of the research re-
ports submitted with the application to
support the proposed labeling." Thus. In
order for a drug to be distributed in in-
terstate commerce for use In children or
pregnant women, sufficient testing must
have taken place in children or pregnant
women to substantiate claims on the
label regarding safety. efflcEicy. and dos-
pge for those groups. If the safe and effi-
cacious dosage for children and preg-
nant women has not been detennlned.
the label must so state. Thus, participa-
tion of children in dioig research might
be the only means of meeting licensing
requirements for new drugs for use In
children, just as studies in pregnant
women might be the only means of meet-
ing licensing requirements for new drugs
for use in that class of patients.
When the risk of a proposed study is
generally considered not significant, and
the potential benefit is explicit, the ethi-
cal issues need not preclude the partici-
pation of children in biomedical re-
search. However, the progression from
innocuous to noxious, in terms of risk,
is often subtle. Therefore, additional re-
view procedures are necessary for re-
search activities which expose children
to risk, in order to provide sharp scru-
tiny, vigorous review, and stringent pro-
cedural safeguards for all subjects of
such research.
Judgments concerning the ethical
propriety of research depend partly upon
the scientific assessment of the potential
risks and benefits. Risk has several im-
portant elements: severity, probability,
frequency, and the timing of possible ad-
verse effects. While it might not always
be easy to distinguish these elements,
they must be evaluated in the assess-
ment of risk, and in the determination of
the acceptable limits of specific risk for
an anticipated benefit. The first judg-
ment to be made is whether it is possible
to assess the risk. If studies in animals
or adults do not provide sufficient infor-
mation to assess these elements of risk,
then the research should not be con-
ducted on children. If the risks can be
determined from studies in animal and
adult humar populations, application to
children may be considered.
In addition to results from investiga-
tions on animals and adult subjects, there
are unknoTvns which must be considered
in the weighing of risk to children. These
include: (1) differences in physiologic or
psychologic response from adult pat-
terns: '2t delayed expression of injury
(for example, until puberty) : (3» effects
on developing organs 'especially the cen-
tral nervous system ) ; ( 4 ) degree of inter-
ference with normal routme required by
the study: and (5) possibility of misuse
of data by institution or school per-
sonnel.
Once the severity and probability of
risks in a particular study have been
identified, a second judgment must be
made; given potential benefits of de-
scribed dimensions, what are the ac-
ceptable limits of risk to which children
ethically may be subjected? Value Judg-
ments which must be weighed here tran-
scend scientific Issues and suggest that
the decision requires interaction among
individuals in society with diverse train-
ing and perspectives. Further, given the
complexity of the Issues and the oppor-
tunity for conflict among the interests of
several parties (the child, the parents or
guardian, the attending physician, and
the research personnel), decisions re-
garding participation of individual sub-
jects in research activities involving chil-
dren should not rest solely with persons
directly involved in the research.
In order to provide both imjjartlal
etliical review of projects and maximum
protection of individual subjects, two
procedures are proposed in addition to
those currently required: review by an
Ethical Review Board at the sponsoring
DHEW agency, and participation by a
Protection Committee at the institution
in which tlie research is to be conducted.
Both groups will provide community In-
volvement in decisions and attempt to
balance scientific value and societal ac-
ce))tabllity of proposed research involv-
ing children.
B. Ethical Revieiv Board: Ethical re-
view of projects. Each DHEW agency
sliall appoint an Ethical Review Board
to provide rigorous review of ethical is-
sues in research involving human sub-
jects by people whose interests are not
solely those of the scientific community.
Its functions will Include:
1. Advising the agency on ethical is-
sues including review of questions of
policy, and development of guidelines
and procedui'es:
2 Fostering inter-agency coherence
through cognizance of the policies and
procedures of other agencies;
3, Reviewing specific proposals or
classes of proposals submitted to the
Board by the agency. These will include
proposals stipulated herein as requiring
review by the Board, as well as proposals
submitted on an ad hoc basis by agency
staff. In addition, the Board may recom-
mend tliat certain additional classes of
research be reviewed.
The acceptabihty of a research project
rests on questions of scientific merit as
well as on questions of ethics. The agency
Primary Review Committees are respon-
sible for evaluating scientific merit and
experimental design. The Etliical Review
Board will be concerned witli ethical is-
sues and questions of societal accepta-
bility in relation to scientific value. In
reaching its determination of acceptabil-
ity, the Board will rely upon the Primary
Review Committees for judgments on
scientific merit and design, existence of
prerequisite animal and adult liuman
studies, estimated risks and benefits
'taking into account the competence
and experience of investigators and the
adequacy of their resources), and scien-
tific importance. It will review proposals
received from these Primary Review
Committees
An investigator proposing research ac-
tivities which expose children to risk
must document, as part of the applica-
tion for support, that the information to
be gained can be obtained in no other
way. The investigator must also stipulate
either that the risk to the subjects will
be Insignificant, or that although some
risk exists, the potential benefit is sig-
nificant and far outweighs that risk. In
no cose will research activities be ap-
proved which entail substantial risk, ex-
cept in the case of clearly therapeutic
procedures in which the benefit to the
patient significantly outweighs the pos-
sible harm. Tlie Ethical Review Board
shall review all proposals approved by
Primary Review Committees involving
children in research activities, except
when the Primary Review Committees
determine that the subjects are not at
risk.
In addition to reviewing ethical Is-
sues, the Board will review procedures
proposed in the research application to
be employed by the institution's Protec-
tion Committee (see below), and may
sugge.'=t modifications of these procedures.
The Board's recommendation may vary
from a general concurrence with the pro-
posal, as submitted by the Investigator.
to a recommendation that each parental
and subject consent must be obtained
with the concurrence of the full Protec-
tion Committee. Any specific recommen-
dations for procedures to be followed by
the Protection Committee will be in-
cluded in the report of the Ethical Re-
view Board which will be forwarded to
the National Advisory Councils or other
secondary review groups of the agency.
Appropriate information will be provided
by the agency to assi'it the Protection
Committee.
Inasmuch as the articulation of deci-
sions might clarify both the objectives
and the assumptions on which they are
based, records of testimony and delibera-
tions, as well as final decisions, should
be maintained pursuant to existing regu-
lations. Such records will serve addi-
tionally as the basis for public account-
ability and will facilitate the review of
any decision, should such action be re-
quested.
Members of the Board, which shall
number 15, shall be drawn from the gen-
eral public, and shall include, for exam-
ple, research scientists (including social
scientists), physicians, lawyers, clergy,
or ethicists. and other representatives of
the public, none of whom shall be em-
ployees of the agency establishing the
Board. Appointments shall be made by
the agency, which will establish the
terms of office and other administrative
procedures of the Board, No more than
'/J of the members of the Board may be
actively engaged in research, develop-
ment, or demonstration activities involv-
ing human subjects,
C. Protection Covimitiee: Protection of
individual subjects. The determination
that it is justifiable to conduct a par-
ticular Investigation in children, how-
ever, does not mean that all children are
equally appropriate subjects for inclusion
in that research. Numerous con.'^idera-
tlons might affect the proper choice of
subjects. Therefore, the sponsoring in-
stitution shall designate a Protection
Committee to oversee: (1 > the process of
FEDERAL REGISTER, VOL. 38, NO, 221 — FRIDAY, NOVEMBER 16, 1973
31742
NOTICES
selection of subjects who may be In-
cluded in the project; (2) the monitor-
ing of their continued willinEness to par-
ticipate In the research: and i3) the de-
sign of procedures to permit Intervention
on behalf of the subject, should that
become necessary. This Committee
should consider the reasonableness and
validity of the consent of the child par-
ticipants (see below* as well as that of
the parents, and should assure that the
issue of risk and discomfort has been
fully and fairly disclosed to parents and
subjects. The procedure employed by the
institution to achieve these goals will
vary: the latitude for such procedures
will be great since it will be related in
part to the issue of risk. Investigatoi-s
proposing research involving children
shall include a deseription of their
planned use of the Protection Committee
in their research proposal : the proposed
use of this Committee will be considered
an integral part of the research proposal
under review by the agency. Relevant in-
formation arising in the review process,
including information about safety, risk,
efficacy, and protection procedures, will
be provided to the Protection Committee
by the agency supporting the research.
One member of the Committee shall be
designated a representative for the proj-
ect to whom any participant (or parent
of a participant! may go to discuss ques-
tions or reservations concerning the
child's continued participation in the
project.
The signature on the consent form of
the Chairman of the Protection Commit-
tee, when all the stipulations and condi-
tions identified above have been met. will
constitute, for DHEW. supplementary
judgment on behalf of the child subject-
The institution's Protection Commit-
tee shall be comprised of at least 5 mem-
bers so selected that the Committee will
be competent to deal with the medical,
legal, social, and ethical issues involved
in the research, and to represent the
community from which the subject popu-
lation is to be drawn. The Committee
should include members of both sexes.
No more than two of the members may
be employees of the institution sponsor-
ing or conducting the research. The Pro-
tection Committee may operate as a sub-
committee of the Organizational Re-
view Committee. The composition of the
Committee must be approved by the
awarding agency.
D. Special provisions — 1. Consent of
both parents. Even where State law may
permit one parent alone to consent to
medical care, both parents have an inter-
est in the ciiild. and therefore, consent
of both parents should be obtained be-
fore any child may participate in re-
search activities. Since the risks of re-
search entail the possibility of additional
burdens of care and support, the consent
of both parents to the assumption of
those risks should be obtained.' except
when the identity or whereabouts of
either cannot be ascertained or either has
been judged mentally incompetent. If the
consent of either parent is not obtained,
written explanation or justification
should be provided to the Protection
Committee. Consent of school or institu-
tional authorities is no substitute for par-
ental concern and consent.
2. The child's consent. An important
addition to the requirement for parental
consent is the consent of the child sub-
ject. Clearly infants have neither the
compi'ehension nor the independence of
judgment essential to consent: older
children might or might not have these
capabiUties. Although children might not
have the capacity to consent on their own
to participate in research activities, they
must be given the opportunity (so far as
they are able* to refuse to participate.
The traditional requirement of parental
corL-^ent for medical procedures is in-
tended to be protective rather than coer-
cive. Thus, while it was held to be un-
lawful to proceed merely with the con-
sent of the child, but without consent of
the parent or legal guardian,' the reverse
should also hold. Therefore, in addition
to consent of both parents, consent of
the child subject must also be obtained
when the child has attained the common
law "age of discretion" of 7 years, unless
the agency Ethical Review Board specifi-
cally exempts a project from this require-
ment.
3. Exclusions. Despite all the protec-
tions afforded by these procedures, cer-
tain children are categorically excluded
from participation in research involving
risk. "These include children with no nat-
ural or adoptive parents available to par-
ticipate in consent deliberations, and
children detained by court order in a
residential facility, whether or not nat-
ural or adoptive parents are available.
E. The fetus. Respect for the dignity
of human life must not be compromised
whatever the age. circumstance, or ex-
pectation of life of the individual. There-
fore, all appropriate procedures provid-
ing protection for children as subjects in
biomedical research must be apphed
with equal rigor and with additional
safeguards to the fetus.
The recent decision of the Supreme
Court on abortion ° does not nullify the
ethical obligation to protect the develop-
ing fetus from avoidable harm. This
obligation, along with the right of eveo'
woman to change her decision regarding
abortion, requires that no experimental
procedures entailing risk to the fetus be
undertaken in anticipation of abortion.
Further, since the fetus might be at risk
in research involving pregnant women,
all research involving pregnant women
must be reviewed by the Ethical Review
Board, unless the Primary Review Com-
mittee determines that the research in-
volves no risk to the fetus. Recruitment
of pregnant subjects for research re-
viewed by the Board must involve the
institution's Protection Committee in a
manner approved by the Board, to pro-
vide supplementary judgment.
'■59 An
2d. Sect. 129. p. 229.
s Bonner v. Moran. 75 U.S. App, D,C. 156.
126 F. 2d 121, 139 A.L.R. 1366 (1941),
'Roe V. Wade, 410 U.S. 113 (1973).
The consent of both parents must be
obtained for any research involving the
fetus, any statutes to the contrary on
consent for abortion notwithstanding.
Both the mother and the father have
an interest in the fetus, and legal re-
sponsibility for it. if it is bom. Therefore,
the father's consent must be obtained
for experimental procedures involving
the fetus: consent of the father may be
waived it his identity or whereabouts
cannot be ascertained, or if he has been
judged mentally incompetent,
rv. Special categories — A. The abor-
tus. Prematurity is the major cause of
infant death in this country; thus, re-
search aimed at developing techniques to
further lability is of utmost importance.
Such research has already contributed
significantly to improvement in the care
of the pregnant woman and of her fetus.
In addition, knowledge of fetal drug
metabolism, enzj-me activity, and the
development of organs is essential to
progress in preventing or offsetting cer-
tain congenital defects. After thorough
research in animal models, it often even-
tually becomes essential to undertake
studies in the non-viable human fetus.
The decision of the Supreme Court on
abortion does not eliminate the ethical
issues involved in research on the non-
viable human fetus. No procedures
should be undertaken on the non-viable
fetus which clearly affront societal
values. Nevertheless, certain research is
essential to improve both the chance of
survival and the health status of pre-
mature infants. Such research must
meet ethical standards as well as show
a clear relation either to the expecta-
tion of saving the life of premature in-
fants through the development of rescue
techniques, or to the furthering of our
knowledge of human development and
thereby our capacity to offset the dis-
abilities associated with prematurity. It
is imperative, however, that the investi-
gator first demonstrate that appropriate
studies on animals have in fact been ex-
hausted and that therefore the research
in question requires that the work be
done on the non-viable human fetus.
Specific reasons for this necessity must
be identified. A thorough review of the
ethical issues in proposed research in-
volving the non-viable fetus is of utmost
importance.
It must be recognized that consent for
abortion does not necessai-ily entail dis-
interest on the part of the pregnant
womsn in what happens to the product
of conception. Some women feel strongly
about what may, or may not. be done to
the aboited fetus; others do not. In order
to give every woman the opportunity to
declare her wishes, consent of the preg-
nant woman for application of any re-
search procedures to the aborted fetus
must be secui-ed at the time of admission
to the hospital for the abortion.
Because research on the abortus in-
volves ethical as well as scientific issues,
all projects involving the abortus must be
reviewed by the Ethical Review Board,
and recniitment of individual pregnant
women for such research must involve
FEDERAL REGISTER, VOL. 38, NO. 221 — FRIDAY, NOVEMBER 16, 1973
NOTICES
3171;^
the institution's Protection Committee in
a manner approved by the Board to pro-
vide supplementary judgment. In addi-
tion to the requirement for maternal
consent, both the Etliical Review Board
and the Protection Committee shall, in
their deliberations, consider the ethical
and social issues surrounding research
on the non-viable fetus. The Protection
Committee must be satisfied that ma-
ternal consent is freely given and based
on full disclosure, each time approved
research is conducted on an abortus.
In order to insure that research con-
siderations do not iniluence decisions as
to timing, method, or extent of a pro-
cedure to terminate a pregnancy, no in-
vestigator engaged in the research on
the abortus may take part in these de-
cisions. Th^e are decisions to be made
by the woman and her physician.
The attending physician, not the in-
vestigator, must determine the viability
of the abortus at the termination of preg-
nancy. If there is a reasonable possibility
that the life of the fetus might be saved,
experimental and established methods
may be used to achieve that goal. Artifi-
cial life-support techniques may be em-
ployed only if the physician of record de-
termines tliat the fetus might be viable.
If the physician determines that tlie
fetus is not viable, it is not acceptable to
maintain heart beat or respu-ation arti-
ficially in the abortus for the purpose of
research. Expeiimental procedures which
of themselves will teniiinate respiration
and heart beat may not be undertaken.
This policy and these protections apply
with equal force to the products of spon-
taneous abortions.
B. The products of in vitro fertilization.
In the interest of improving human
health and development, the biology of
human fertilization and the early events
surrounding tiiis phenomenon, including
Implantation, should be studied. To the
extent that in vitro studies of human
fertUization might further this aim, they
are permissible at the present time with-
in the limits outlined below.
Current technology limits the in vitro
development of the human fertilized
ovum to a period of several days. This is
a rapidly advancing field of biomedical
research, however, and the time might
come when it is possible to extend in
vitro development beyond the stage of
early cell division and possibly even to
vlabihty.
It is contrary to the interests of so-
ciety to set permanent restrictions on
research which are based on the suc-
cesses and limitations of current tech-
nology. Still, it is necessai-y to impose
restraints prospectively in order to pro-
vide reasonable protections, while at tlie
same time permitting scientific advance-
ments which might well benefit society.
A mechanism is required to weigh, at any
given time, the state of the art. a specific
proposal, legal issues, comjnunity stand-
ards, and the availabihty of guidelines to
govern the research situation. Tliis
mechanism is provided by the Ethical
Review Board. Ultimately, the Board
will determine the acceptability of a
project involviJ-ig in vitro fertilization,
and by recognizing the state of the art, as
well as societal concerns, propose ap-
propriate research policy.
Care must be taken not to bring hj-
man ova fertilized in vitro to viability — •
whether in the laboratory or implanted
in the uterus — until the safety of the
technique has been demonstrated as far
as possible in sub-human primates. To
this end:
1. All proposals for research involving
human In vitro fertilization must be re-
viewed by the Ethical Review Board.
2. No research involving the implanta-
tion of human ova fertilized in the lab-
oratory into recipient women should be
supported until the appropriate scientific
review boards are satisfied that there has
been sufficient work in animals (includ-
ing sub-human primates) to demon-
strate the safety of the teclinique. It is
recommended that this determination of
safety include studies of natural bom
offspring of the products of in vitro
fertilization.
3. No Implantation of human ova
fertilized in the laboratory should be
attempted until guidelines are developed
governing the responsibilities of the do-
nor and recipient "parents" and of re-
search institutions and personneL
V. Prisoners — A. Policy coTisideratioiis.
Clinical research often requires the par-
ticipation of normal volunteers; for ex-
ample, in the early stages of drug or
vaccine evaluation. Sometimes, the need
for standardization certain variables, or
for monitoring responses over an ex-
tended period of time, requires that the
subjects of research remain in a con-
trolled environment for the duration of
the project. Prisonei-s may be especially
suitable subjects for such studies, since,
unlike most adults, they can donate their
time to research at virtually no cost to
themselves. However, the special status
of prisoners requires that they have
special protection when they participate
in research.
While there is no legal or moral objec-
tion to the participation of normal vol-
unteers in research, there are problems
sun-Qunding the participation of volun-
teers who are confined in an institution.
Many aspects of institutional life may
influence a decision to participate: the
extent of that influence might amount to
coercion, whether it is intended or not.
Where there are no opporiunities for
productive activity, research projects
might offer relief from boredom. Wliere
there are no opportunities for earning
money, research projects offer a source
of income. Where living conditions are
unsatisfactory, research projects rmght
offer a respite in the form of good food,
comfortable bedding, and medical atten-
tion. While this is not necessarily wrong,
the inducement (compared to the depri-
vation) might cause prisoners to offer to
participate in research which would ex-
pose tliem to risks of pain or incapacity
which, under normal circumstances, they
would refuse. In addition, there is al-
ways the possibility that the prisoner will
expect participation in research to be
viewed favorably, and to his advantage,
by prison authorities (on whom his other
few privileges depend) and by the parole
board 'on whom his eventual release de-
pends) . This is especially true when the
research involves behavior modification
and may be termed "therapeutic" with
respect to the prisoner. In such instances,
participation inevitably can-ies with it
tlie hope that a successful result will in-
crease the subject's chances for parole.
Thus, the inducement involved in thera-
peutic research might be extremely diffi-
cult to resist: and for this reason, special
protection is necessary for prisoners par-
ticipating in research, whether or not the
research is therapeutic.
The first principle of the Nureniburg
Code requires that subjects of biomedical
research must be "so situated as to be
able to exercise free power of choice"
concerning their participation. Whether
prisoners can be considered to be "so
situated" is ultimately a matter for the
courts and the legislatures to resolve. In
the meantime. It must be recognized that
where liberty is limited, and where free-
dom of choice Is restricted, there Is a
corresponding limitation of the capacity
to give truly voluntary consent. Although
the prisoner might be adequately In-
formed, and competent to make judg-
ments, the voluntariness of the person's
consent remains open to question. This
policy statement is designed to provide
additional protections to prisoners par-
ticipating in research.
The mission of the Department of
Health, Education, and Welfare does not
include rendering judgments on the ad-
ministration of justice or the manage-
ment of the correctional system. At the
same time, the Department should not
support activities which take unethical
advantage of those who are under the
jurisdiction of the courts and who. for
that reason, lack some of the usual de-
fenses to tlieir personal integrity. Partici-
pation of prisoners in the research activ-
ities of the DHEW in the pursuit of medi-
cal knowledge might be beneficial to all
concerned, but the relationship which
involves a class of persons with dimin-
ished autonomy requires careful super-
vision.
Many prisoners are strongly motivated
to participate in research, and view as
unfair suggestions that they be denied
this opportunity. Unless society, tiirough
its judicial and legislative bodies, decides
that such participation should be halted.
It is essential to develop mechanisms to
protect those who may participate, or
who are now participating, from the co-
ercive aspects of incarceration wliich
diminish tlieir capacity for voluiitary
consent. Pui'suant to the obligation to
protect the rights of all subjects partici-
pating in research conducted under its
auspices, the DHEW is proposing special
guidelines for the protection of prison-
ers as subjects in any biomedical or be-
havioral research.
Two aspects o'f research involving
prison populations require special review
and procedural safeguards in addition to
those provided by current DHEW policies.
FEDERAL REGISTER, VOL. 38, NO. 221— FRIDAY. NOVEMBER 16, 1973
31744
NOTICES
First, when research Is conducted under
the auspices of a commercial manufac-
turer or an Individual Investigator, It Is
not always subject to review by an Or-
ganizational Review Committee, as Is re-
quired for similar research conducted at
a hospital or a university. Thus, local
review has not heretofore been required
for ethical considerations or tor specific
problems related to the population or In-
stitution which is to be directly Involved.
Second, because of the loss of Individual
dignity, the limitations of personal free-
dom, and the possibility of real or poten-
tial coercion which may accompany con-
finement In an Institution, special safe-
guards must be provided to mitigate the
Inequalities of bargaining power between
the prisoners and those who are in posi-
tions of authority. While It is Important
that prisoners have the opportunity to
participate in research, it Is equally Im-
portant that they not feel compelled to
do so.
B. Organizational Review Committee.
All research involving prisoners must be
conducted at an accredited correctional
facility (see Section F, below) and be re-
viewed Initially, and on a continuing
basis, either by the Organizational Re-
view Conunlttee of that correctional fa-
cility or by the Organizational Review
Committee of the Institution sponsoring
the research. The Organizational Review
Committee shall have the duties and re-
sponsibilities identified In current DHEW
regulations. In addition, for each project,
it siiall determine the adequacy of clinic
or hospital facilities for the particular
activity to be conducted, assess the ap-
propriateness of the subject population
for that activity, and weigh the questions
of scientific importance, social need, and
ethical acceptability. In addition to the
foregoing, the Organizational Review
Committee shall have the following du-
ties, with respect to research involving
prisoners as subjects;
1. To review and approve or modify
the process proposed by the principal
investigator for involvement of the Pro-
tection Committee (see below) in over-
seeing the selection of subjects who may
be Included In the research, and the proc-
ess of obtaining their voluntary and In-
formed consent.
2. To set rates of remuneration, if any,
consistent with the expected duration
and discomfort or rtsk of the proposed
study, and consistent with other oppor-
tunities for employment, if any, at the
facility In question.
3. To monitor the progress of the re-
search as required by the sponsoring
DHEW agency.
The recommendations of this Com-
mittee, along with a report describing
any site visits, shall be Included with the
investigator's application to the agency.
For facilities which have filed no gen-
eral assurance, composition as well as
recommendations of the Organizational
Review Committee will be considered an
integral part of the proposal in the
agency review.
C, Protection Committee. The primary
function of the Protection Committee Is
to provide supplementary Judgment by
overseeing the selection of subjects who
may be included in a research project to
assui'o that their consent is as voluntary
as possible uiider the conditions of con-
finement.
Consent Is a continuing process. To
assure the voluntariness of consent, sub-
jects must be able to withdraw from
the research project without prejudice.
Each Protection Committee shall estab-
lish such a withdrawal mechanism.
The duties of the Protection Commit-
tee, therefore, shall include:
1. Reviewing the Information given
the potential subjects, with special atten-
tion to: adverse effects, the Importance
of reporting all deviations from normal
function, the continuing option of with-
drawing from participation at any time,
and the identification of a member of the
committee who will be available, at rea-
sonable intervals upon request, for con-
sultation regarding the research project.
All of this information shall appear on
the consent form, a copy of which will
be given to each participant. When oral
representations are made procedures de-
scribed under DHEW regulations shall
be followed.
2. Overseeing the process of selection
of subjects who may be Included in the
research, to the extent stipulated in the
recommendation of the Organizational
Review Committee. This may vary from
overall approval of the recruitment proc-
ess, to reviewing a sample of subject
selections, to Interviewing as a full Com-
mittee each individual subject to be in-
cluded In the project.
3. Visiting the Institution on a regular
basis to Invite questions, to monitor the
progress of the research, and to assess
the continued willingness of subject par-
ticipation. The frequency of these visits
will be determined by the nature of the
research, and any recommendations of
the Organizational Review Committee.
Depending upon the circumstances and
the number of subjects involved, ihese
visits may be made either on a rotating
basis by various members of the Commit-
tee, or by the full Committee.
4. Maintaining records of Its activities
including contacts initiated by subjects
in the project between regular site visits.
These records shall be made available to
the agency upon request.
The Protection Committee shall be
comprised of at least B members so se-
lected that the Committee will be compe-
tent to deal with the medical, legal, so-
cial, and ethical Issues involved. No more
than 1/3 of the members shall be scientists
engaged in biomedical research or physi-
cians; at least 1 shall be a prisoner or a
representative of an organization con-
cerned with the prisoners' Interests; no
more than 1 (except prisoners or their
representatives) shall have any affiliation
with the prison facility or with the unit
of government having Jurlsdicilon over
the facility, with the exception of persons
employed by the department of education
of a relevant Jurisdiction in a teoclilng
capacity. The composition and the inves-
tigator's proposed use of the Committee
must be reviewed and approved by the
DHEW agency.
D. Payment to prisoners. The amount
paid for participation In research will
vary according to the risks and discom-
forts Involved, and the other employment
opportunities in the facility in which the
research Is to be conducted. The specific
amount for each project will be deter-
mined by the Organizational Review
Committee, which will forward its rec-
ommendation as part of the application
to the sponsoring agency. The amount
paid shall provide a compensation for
services, but shall not be so great as to
constitute undue Inducement to partici-
pate.
Any reduction of sentence as a conse-
quence of participation in research shall
be comparable to other opportunities at
the facility for earning such a reduction.
Any subject who is required by the in-
vestigator or prison physician to with-
draw, for medical reasons, before com-
pletion of the investigation, shall con-
tinue to be paid for a period to be deter-
mined by the Protection Committee in
consultation with the Investigator. This
does not apply to subjects who withdraw
for other reasons. Any disputes regarding
certification of withdrawal for medical
reasons shall be heard and resolved by
the Protection Committee.
Prisoners who serve on the Protection
Committee shall be paid an amount con-
sistent with that received by the research
subjects.
E. Accreditation. The Secretary.
DHEW. shall establish standards for ac-
creditation of correctional facilities of-
fering to act as sites for the performance
of clinical research, or offering to act as
a source of volunteer subjects for clinical
research when the research Is supported
in whole or In part by Departmental
funds or the research is to be performed
in compliance with requirements of Fed-
eral statutes.
The review for certification shall In-
clude, but not be limited to:
1. Standard of living in the prison
facility.
2. Other opportunities for employ-
ment and/or constructive activity, either
within the prison, or in a work-release
program.
3. Adcguacy of (a) medical care for
the general prison population (so that
participation in research is not the only
means of obtaining medical attention),
and (b) the proposed methods for main-
taining medical records and for protect-
ing the confidentiality of those records.
4. The nature, structure, function, and
composition of the Organizational Re-
view Committee (whether located at the
prison or at the Institution sponsoring
the research) which is to review clinical
research in that correctional facility.
The Secretary shall also set general
guidelines to assist the Organizational
Review Committees In determining rates
of remuneration, and shall Indicate
groups who may be considered to repre-
sent the prisoners' interests for the pur-
pose of appointment to membership on
the Protection Committee. No institution
shall be accredited if research, whether
or not supported by funds from the
DHEW, is conducted under its auspices.
FEOEKAL REOISTER, VOL, 38, NO, S21— FRIDAY, NOVEMBER 16, 1973
NOTICES
31745
or by members of its staff, which is not
in conformity with these ^uideUnes. No
DHEW funds will be granted for research
in institutions lacking such accreditation.
F. Special provisions. 1. Persons de-
tained in a con-ectional facility while
awaiting sentence, or in a hospital fa-
cility for pre-sentence diagnostic obser-
vation, are excluded from participation
in research.
2. A child may not be included as a
subject in research involving risk if he
is detained in an institutional setting
pursuant to a court order, whether or not
the parents and the child have consented
to the child's participation.
VI. The mentally infiTm.—A. Policy
considerations. The institutionalized
mentally infirm are doubly limited with
respect to participation in research ac-
tivities. First. ELS with children, they
might lack the clear capacity to com-
prehend relevant information, and to
make informed judgments concerning
their participation. Second, as with pris-
oners, they experience a diminished
sense of personal integrity as a result of
confinement in an institution. Such con-
finement restricts their freedom of choice
and Imposes elements of coercion, which
limit their capacity to give truly volun-
tary consent. In addition, the mentally
Infirm who are confined in institutions
have more pressures to cooperate with
custodial authorities than do prisoners.
for their release might depend entirely
upon theii- behavior and on the impres-
sion they make upon those having the
power to make decisiohs concerning ter-
mination of their confinement.
Legal guardians, who have authority
to consent for medical treatment, might
have interests in the matter which do
not necessarily coincide with those of
the patient. Long-term management of
patients with mental disabilities is ex-
pensive and time-consuming. Any pro-
posal wliich might reduce either the ex-
pense or the supervision required in
caring for such persons might be appeal-
ing, whether or not there is correlative
benefit to the patient. This is certainly
the case in projects offering new ther-
apy; it might also occur, albeit in a more
subtle form, where free medica,l or cus-
todial services are perceived to be con-
tingent upon the patient's participation
as a subject in research.
The courts have begun to recognize
that persons confined in institutions
might not be able to give truly voluntary
consent in such matters. It is important
to recognize, as well, that persons en-
cumbered with the economic or custodial
responsibility for the mentally infirm
might not be sufficiently objective to
make judgments which are fully in the
best interest of the institutionalized per-
son.
The circumstances are limited under
which it is justifiable to include the men-
tally infirm as subjects in biomedical re-
search. These circumstances include
projects in which: the proposed research
concerns diagnosis, treatment, preven-
tion, or etiology of the disability from
which they suffer; the necessary infor-
mation can be obtained only from those
subjects; or the studies concern institu-
tional Ufe per se. With these exceptions,
the general i-ule is that the participation
of the mentally infirm as subjects in re-
search is not acceptable.
B. Ethical review of projects and pro-
tection of subjects. In instances in which
a research protocol requires the partici-
pation of mentally infirm subjects, the
research must be overseen by a Protec-
tion Committee in the manner described
in Section ITI-C, pertaining to children.
This Protection Committee must be sup-
ervised on a continuing basis, as de-
scribed in Section V-B, by the Organiza-
tional Review Committee of the institu-
tion in which the research is to be con-
ducted or of the institution sponsoring
the research.
vn. General provisions. These pro-
visions apply to all research activities
covered by this policy.
A. Referrals to the Ethical Review
Board. Whenever a Primary Review
Committee, secondary review group, or
the agency staff perceives an apparent
and significant question of ethics or an
unusual element of risk — whatever the
subject group involved — the research
proposal in question may be foi-warded
to the Ethical Review Board for an opin-
ion. In addition to offering an opinion of
acceptability from an ethical viewpoint,
the Board may choose to re.commend the
establishment of a Protection Commit-
tee, and suggest guidelines for its opera-
tion.
B. Procedures requiring special con-
sideration. All other recommendations
notwithstanding, DHEW may Identify
certain procedures which: (1) Require
Protection Committee review of the se-
lection of each individual subject; (2)
are acceptable for stipulated subjects
only if approved by affirmative declara-
tory judgment of a court of competent
jurisdiction; or (3> are unacceptable.
C. Research conducted in Foreign
Countries. All regulations governing re-
search conducted in the United States
apply to research conducted in foreign
countries under DHEW auspices, and
the ethical review must be of equal rigor.
There are sometimes special con-
straints encountered in foreign settings.
Therefore, in addition to the require-
ment that consent procedures for re-
search to be conducted abroad conform
with the policy and regulations set forth
in this document, there must be written
assurance that the proposed research
enjoys local acceptance, and offends no
local ethical standards.
D. Research submitted pursuant to
DHEW regulatory requirements. Re-
search or testing which is performed
pursuant to or in fulfillment of any reg-
ulation issued by any agency of the
DHEW will be acceptable to the govern-
ment only if conducted in compUance
with these procedures and regulations.
E. Clinical research not funded by
DHEW.
If. In the Judgment of the Secrefary, an
organization has failed to comply with the
terms of this policy with respect to a par-
ticular DHEW grant or contract, he may
require that said grant or contract be ter-
minated or suspended In the manner pre-
scribed in applicable grant or procurement
regulations.
If. in the Judgment of the Secretary, an
organization fails to discharge Its responsi-
bilities for the protection of the rights and
welfare of the subjects in Its care, whether
or not DHEW funds arc involved, he may.
upon reasonable notice to the organization
of the basis for such action, determine that
Its eligibility to receive further DHEW grants
or contracts involving human subjects shall
be terminated. Such disqualification shall
continue until It is shown to the satisfaction
of the Secretary that the reasons therefor
no longer exist.
If, in the Judgment of the Secretary, an
individual serving as principal investigator,
program director, or other person having
responsibility for the scientific and technical
direction of a project or activity, has failed
to discharge his responsibilities for the pro-
tection of the rights and welfare of human
subjects in his care, the Secretary may. upon
reasonable notice to the Individual of the
basb? for such action, determine that such
individual's eligibility to serve as a princi-
pal Investigator or program director or in
another similar capacity shall be terminated.
Such disqualification shall continue until It
Is shown to the satisfaction of the Secretary
that the reasons therefor no longer exists
In reaching a determination on com-
pliance, with respect to subjects with
limited capacity for consent, the Secre-
tary will consider the extent and the
nature of the procedures by which the
institution offers protection in all studies
conducted in or by that institution re-
gardless of the soiu-ce of fimds. with the
expectation that there shall be an ethical
review similar to that required of the
agency Ethical Review Board (IH-B).
The existence of a Protection Commit-
tee, overseen by an Organizational Re-
view Committee and acting to afford sup-
plementary judgment, will be accepted
as evidence of responsibility in this
regard.
F. Confidentiality of information and
records. Nothing in this policy shall be
construed as permitting the release of
confidential research protocols nor the
violation of State law applicable to the
confidentiaJity of Individual medical
records.
Vrn. Draft additions to proposed reg-
ulations (See Federal Register, Vol. 38,
No. 194. E>art 2, Tues.. Oct. 9. 1973. pp.
27882-27885).
To amend the proposed Part 46 of Sub-
title A of Title 45 of the Code of Fed-
eral Regulations by deleting §§46.20
through 46 23. redesignating §§46.1
through 46.19 thereof as Subpart A. and
adding the following new Subparts B
through F:
Subpart B — ADorrroNAL Protections for
Children Involved as Subjects in DHEW
Activities
Sec.
46 21 Applicability.
46.22 Purpose.
46.23 Need for legally effective consent.
4624 Definitions,
4625 Ethical Review Board; Composition:
Duties
No. 221— Pt, n-
FEDERAL REGISTER, VOL, 38, NO. 221 — FRIDAY, NOVEMBER 16, 1973
31746
NOTICES
46-26 Protection Committees; Composition;
I>utles.
46 27 CertBin children excluded from par-
ticipation In DHEW supported ac-
46-31 Applicability.
46 32 Purpose.
46 33 Deflnltlons-
4634 Duties of the Ethical Review Board,
46 35 Maternal consent to activities involv-
ing the abortus
46.36 Additional conditions for activities
involving the abortus.
46-37 Prohibition on certain activities In-
volving pregnant women where the
fetus may be adversely aJIected.
46.38 Parental consent to activities which
may affect the fetus.
46 39 Activities to be performed outside the
United States.
SOBPABT I>~ADDmONAL PROTECTIONS POR
Prisoners Involved as Sxjbjects in DHEW
Activities
46.41 Applicability.
46.42 Purpose.
46.43 Definitions.
46-44 Additional duties of Organizattonal
Review Committee where prisoners
are involved.
46,45 Protection Committees; Duties; Com-
position.
46 46 Prohibition on participation in activi-
ties prior to conviction.
46.47 Remuneration to subjects.
46.48 Accreditation.
46.49 Activities to be performed outside the
United States.
Subpart E — Additional Protections for the
Institutionalized Mentally Infirm In-
volved as Subjects in DHEW Activities
4651 Applicability.
46.52 Purpose.
46.53 Definitions.
46-54 Limitations on activities involving the
institutionalized mentally Infirm.
46-55 Additional duties of Organizational
Review Committee where the men-
tally Infirm are mvolved
46,56 Protection Committees; Duties; Com-
position.
46-57 Activities to be performed outside the
United States.
Sub
■ F— Gen
, Provisions
46-61 Applicability.
46-62 Organization's records.
46.63 Reports.
46 64 Early termination of awards; sanctions
lor noncompliance.
46.65 Conditions.
AuTHORrrv: 5 U.SC. 301.
STTBPART B ADDmONAL PROTECTIONS FOR
Children Involved as Subject In DHEW
ACTIYITIES
Section 46-21 Applicability, (a) The regu-
lations In this subpart are applicable to all
Department of Health, Education, and Wel-
fare research, development, or demonstra-
tion activities In which children may be at
risk,
(b) The requirements of this subpart are
In addition to those imposed under subpart
A of this part.
Section 46-22 Purpose It Is the purpose
of this subpart to provide additional safe-
guards in reviewing activities to which this
subpart Is applicable Inasmuch as the poten-
tial subjects in activities conducted there-
tinder ml(^ht be unable fully to comprehend
the rLslcs which might be involved and arc
legally Incapable of consenting to their par-
ticipation m such activities.
Section 46.23 Need /or legally effective
consent- Nothing in this subpart shall be
construed as indicating that compliance with
the procedures set forth herein will neces-
sarily result in a legally effective consent
under applicable State or local law to a sub-
ject's participation in any activity; nor In
particular does It obviate the need for court
approval of such participation where court
approval Is required under applicable State
or local law In order to obtain a legally ef-
fective consent.
Section 46 24 Definitions. As used In this
(a) -DHEW activity means:
(U The conduct or support (through
grants, contracts, or other awards) of bio-
medical or behavioral research involving
human subjects; or
(2) Research, development, or demon-
stration activities regulated by any DHEW
agency.
(b) "Subject at risk" means any Individ-
ual who might be exposed to the possibility
of harm — physical, psychological, sociologi-
cal, or other — as a consequence of partici-
pation as a subject In any DHEW activity
which goes beyond the application of those
established and accepted methods necessary
to meet his needs
(c) "Child " means an Individual who has
not attained the legal age of consent to
participate in research as determined under
the applicable law of the jurisdiction in
which such research is to be conducted
(d) "DHEW means the Department of
Health, Education and Welfare
Section 46 25 Agency Ethical Rei-iew
Board: composition; duties (a) The head of
each agency shall establish an Ethical Re-
view Board, hereinafter referred to as the
"Board," to review proposals for research, de-
velopment, and demonstration activities to
which this subpart Is applicable, as well as
to advise him or her on matters of policy
concerning protection of human subjects.
The Board shall be composed of research
scientists (biomedical, behavioral, and/or
social), physicians. lawyers, clergy, ethlcists,
and represent-atlves of the public It shall
consist of 15 members appointed by the
agency head from outside the Federal Gov-
ernment. No more than one-third of the
members may be individuals engaged In re-
search, development, or demonstration
activities involving human subjects
(b) It shall be the function of the Board
to review each proposed activity to which
this subpart applies, and advise the agency
concerning the acceptability of such activ-
ities from the standpoint of societal need
and ethical considerations, taking Into ac-
count the assessment of the appropriate
Primary Review Committees as to: (1) The
potential benefit of the proposed activity,
(2) scientific merit and experimental de-
sign, (3) whether the proposed activity
entails risk of significant harm to the sub-
ject. (4) the sufficiency of animal and adult
human studies demonstrating safety and
clear potential benefit of the proposed pro-
cedures and providing sufficient information
on which to base an assessment of the risks,
and (5) whether the information to be
gained may be obtained from further animal
and adult human studies,
(c) The Board shall review the procedures
proposed by the applicant to be followed by
the Protection Committee, provided for in
§46 26 of this subpart, in carrying out Its
functions as set forth in § 46 26 In addition,
the Board may recommend additional func-
tions to be performed by the Protection
Committee in connection with any particular
activity.
(d ) In decisions regarding activities
covered by thlB subpart, the agency shall
take into account the recommeudations of
the Board.
Section 46.26 Protectwn Committees; com-
position, duties, (a) No activity covered by
this subpart will be approved unless it pro-
vides for the establishment by the applicant
of a Protection Committee, composed of at
least five members so selected that the Com-
mittee will be competent to deal with the
medical, legal, social and ethical issues in-
volved In the activity. None of the members
shall have any association with the pro-
posed activity, and at least one-half shall
have no as.socJatton with any organization or
Individual conducting or supporting the
activity. No more than one-third of the
members shall be individuals eng.^ged in
research, development, or demonstration
activities involving human subjects. The
composition of the Protection Committee
shall be subject to DHEW approval.
(b) The duties of the Protection Commit-
tee, proposed by the applicant, and reviewed
by the agency including the Ethical Review
Board shall be to oversee: (l> Tlie selection
of subjects who mav be Included in the
activity; (2) the monitoring of the snbject's
continued willingness to participate in the
activity; (3) the design of procedures to per-
mit Intervention on behalf of one or more
of the subjects If conditions warrant; (4) the
evaluation of the reasonableness of the par-
ents' consent and ( where applicable i the
subject's consent; and (5) the procedures frr
advising the subject and/or the parents con-
cerning the subject's continued participation
In the activity. Each subject and his or her
parent or guardian will be informed of the
name of a member of the Protection Com-
mittee who will be available for cons\ilta-
tion concerning the activity.
(c) The Protection Committee shall estab-
lish rules of procedure for condiicting its
activities, which must be reviewed by DHEW.
and shall conduct its activities at convened
meetings, minutes of whicii shall be prepared
and retained.
Section 46-27 Certain children excluded
from participation in DHEW activities. A
child may not be Included as a subject in
DHEW activities to which this subpart is ap-
plicable If:
(a) TTie child has no known living parent
who Is available and capable of participating
in the consent process: Provided. That this
exclusion shall be inapplicable if the child
Is seriously ill, and the proposed research Is
designed to substantially alleviate his con-
dition; or
(b) The child has only one known living
parent who is available and capable of par-
ticipating in the consent process, or only one
such parent, and that parent has not given
consent to the child's participation in the
activity; or
(c) Both the child's parents are available
and capable of participating In the consent
process, but both have not given such con-
(d) The child Is Involuntarily confined In
an institutional setting pursuant to a court
order, whether or not the parents and child
have consented to the child's participation In
the activity; or
(e) The child has not given consent to his
or her participation in the research: Pro-
rided. That this exclusion shall be inapplica-
ble if the child Is 6 years of age or less or
If explicitly waived by the DHEW; or
(f) The Protection Commiitee established
under § 46 26 of this subpart has not reviewed
and approved the child's participation In the
activity.
Section 46.28 Activities to be performed
outside the United States. In addition to sat-
isfying all other applicable requirements In
FEDERAL REGISTER, VOL 38, NO. 221 — FRIDAY, NOVEMBER 16, 1973
NOTICES
this subpart, an activity to which this sub-
part Is applicable, which Is to be conducted-
outside the United States, must Include
written documentation satisfactory to DHEW
that the proposed activity is acceptable under
the legal, social, and ethical standards of the
locale in which It is to be performed.
Section 46,31 Applicability, (a) The regu-
lations In this subpart are applicable to all
Department of Health. Education, and Wel-
fare research, development, or demonstration
activities: (1) Involving pregnant women,
unless there is a finding by DHEW that the
activity will have no adverse effect on the
fetus, or is clearly thereapeutlc with respect
to the fetus involved, (2) involving the abor-
tus or the non-viable fetus, or (3) involv-
ing in vitro fertilization of human ova.
(b) Nothing in this subpart shall be con-
strued as Indicating that compliance with
th© procedures set forth herein will in any
way render inapplicable pertinent State or
local laws bearing upon activities covered
by this subpart.
(c) To the extent the requirements of sub-
part A of this part are applicable to activities
also covered by this subpart, the require-
ments of this subpart are in addition to
those imposed under subpart A.
Section 46,32 Purpose. It is the purpose of
this subpart to provide additional safeguards
In reviewing activities to which this subpart.
is applicable to assure that they conform to
appropriate ethical standards and relate to
important societal needs.
Section 46.33 Definitions. As used In this
subpart ;
(a) "DHEW" means the Department of
Health. Education, and Welfare.
(b) "DHEW activity'* means:
(1) The conduct or support (through
grants, contracts, or other awards) of bio-
medical or behavioral research Involving hu-
man subjects: or
(2) Research, development, or demonstra-
tion' activities regulated by any DHEW
agency.
(c) "Board^ means the Board established
under § 46.25,
(d) "Protection Committee" means a com-
mittee referred to in § 46 26
(e) "Pregnancy" means the period of time
from implEintation of a fertilized ovum until
delivery.
(f) "Petus" means the product of concep-
tion from implantation until delivery
(g) "Abortus" means the fetus when it has
been expelled whole, whether spontaneously
or as a result of medical or surgical inter-
vention to terminate a pregnancy, prior to
viability. This definition, for the purpose of
this policy, excludes the placenta, fetal
material which is macerated at the time of
expulsion, a dead fetus, and isolated fetal
tissue or organs excised from a dead fetus.
(h) "Viability of a fetus" means capabil-
ity given the benefit of available therapy, of
Independently maintaining heart beat and
respiration.
(1) "In vitro fertilization" means any fer-
tilization of human ova which occurs outside
the body of a female, through admixture of
human sperm and such ova
Section 46.34 Duties of the Ethical Re-
view Board, (a) It shall be the function of
the Board to review each activity to which
this subpart applies and advise the agency
concerning the acceptability of such activi-
ties from the standpoint of societal need and
ethical considerations, taking into account
the assessment of the appropriate Primary
Review Committees as to: (I) The potential
benefit of the proposed activity. (2) scien-
tific merit and experimental design, (3) the
sufficiency of studies Involving animals dem-
oiistratlng the clear potential benefit of the
proposed procedures and (4) whether the
information to be gained may be obtained
from further animal or adult human studies.
(b) The Board may recommend the estab-
lishment by the sponsoring institution of a
Protection Committee to carry out such func-
tions as the Board deems necessary.
Section 46.35 Maternal consent to activ-
ities involving the abortus, (a) No activity to
which this subpart Is applicable may Involve
an abortus or a non-viable fetus unless ma-
ternal consent has been obtained
(b) No activity to which this subpart is
applicable may involve an abortus or a non-
viable fetus unless: (1) Individuals involved
in the activity will have no part in the de-
cision as to timing, method, or extent of the
procedure used to terminate the pregnancy,
or in determining viability of the fetus at
the termination of the pregnancy; (2) vital
functions of the abortus will not be main-
tained artificially for purposes of research:
and (3) experimental procedures which
would terminate heart beat or respiration in
the abortus will not be employed
Section 4637 Prohibition on certain ac-
tivities involi>i7ig pregnant women ivhere the
fetus may be adversely affected. The Board
shall review all research, development, and
demonstration activities involving pregnant
women. No activity to which this subpart is
applicable may involve a pregnant woman if
the Primary Review Committee finds that the
fetus might be adversely affected, unless the
primary purpose of the activity is to benefit
that fetus. In addition, no activity to which
this subpart is applicable may involve preg-
nant women unless all the requirements of
this subpart are satisfied.
Section 46 38 Parental consent to activi-
ties which might affect the fetus. No activity
involving a pregnant woman which might
affect the fetus but which nevertheless is
permissible under 5 46 37 shall be conducted
unless maternal consent has been obtained,
as well as the consent of the father If he is
available and capable of participating in the
consent process.
Section 46,39 Activities to be perjorined
outside the United States. In addition to
satisfying all other applicable requirements
in this subpart, activities to which this sub-
part is applicable, which are to be conducted
outside the United States, must include writ-
ten documentation satisfactory to DHEW
that the proposed activity Is acceptable under
the legal, social, and ethical standards of the
locale in which it is to be performed.
SUBPART D — Additional Protections for
Prisoners Involved as Subjects in DHEW
Section 46.41 Applicability, (a.) The regu-
lations in this subpart are applicable to all
l>epartment of Health, Education, and Wel-
fare research, development, and demonstra-
tion activities involving prisoners as subjects,
(b) The requirements of this subpart are
in addition to those imposed under subparts
A and B of this part.
Section 46 42 Purpose. It is the purpose of
this subpart to provide additional safeguards
for activities to which this subpart is appli-
cable inasmuch as the potential subjects in
activities conducted thereunder, because of
their incarceration, might be under con-
straints which could affect their ability to
make a truly voluntary and uncoerced de-
cision whetlier or not to participate in such
activities.
Section 46,43 Definitions. As used in this
subpart:
(a) "DHEW activity" means:
(1) the conduct or support (through
grants, contracts, or other awards) of bio-
medical or behavioral research involving
human subjects; or
(2) research, development, or demonstra-
tion activities regulated by any DHEW
agency.
(b) "Prisoner" means any Individual In-
voluntarily confined In a penal institution.
The term is intended to encompass individ-
uals sentenced to such an institution under
a criminal or civil statute and also Individ-
uals detained by virtue of statutes which
provide alternatives to criminal prosecution.
(c) "DHEW" means the Department of
Health. Education, and Welfare
Section 46,44 Additional duties of Organi-
sati07ial Revtciv Coimnittee where prisoners
are involved, (a) In carrying out Its responsi-
bilities under subpart A of this part for activ-
ities also covered by this subpart, the Organi-
zational Review Committee provided for un-
der subpart A shall also certify: (1) That
there will be no undue inducements to par-
ticipation by prisoners as subjects In the ac-
tivity, taking into account among other fac-
tors, the sources of earnings generally avail-
able to the prisoners as compared with those
offered to participants In the activity. (2)
that the clinic and hospital facilities are ade-
quate for the proposed activity, (3) that all
aspects of the activity would be appropriate
for performance on nonprlsoners. and (4)
that no prisoner will be offered any reduction
in sentence or parole for participation in
such activity which is not comparable to that
offered for other activities at the facility not
of a research, development, demonstration or
similar nature.
(b) In addition, the Organizational Re-
view Committee shall have the following
duties: (1) To review, approve, or modify th©
procedures proposed for the Protection Com-
mittee in carrying out its functions as set
forth in I 46.45; (2) To recommend any addi-
tional functions to be performed by the Pro-
tection Committee in connection with a par-
ticular activity: (3) To set rates of remunera-
tion, if any, consistent with the anticipated
duration, discomfort, and/or risk of the ac-
tivity but not in excess of that paid for other
employment generally available to inmates
of the facility in question; and (4) To carry
out such other responsibilities as may be
stipulated by DHEW in the contract or grant
award,
(c) Activities to which this subpart is ap-
plicable must provide for the designation of
an Organizational Review Committee, where
no such Committee has been established
under subpart A.
Section 46.45 Protection Committees;
duties; composition, (a) No activity covered
by this subpart will be approved unless it
provides for the establishment of a Protec-
tion Committee to carry out the following
functions, as well as any others recommended
by the Organizational Review Committee or
by DHEW: (1) Reviewing the procedure for
soliciting participation by prisoners m the
research activity to determine that all ele-
ments of informed consent, as outlined in
§ 46 3. are satisfied; (2) overseeing the selec-
tion of prisoners who may participate In the
activity; (3) monitoring the progress of the
research and the continued willingness of
subject participation; and (4) Intervening
on behalf of one or more subjects if condi-
tions warrant. In addition, each subject will
be informed of the name of a member of the
Protection Committee who will be available
to the subject for consultation concerning th©
activity.
(b) Each Protection Committee shall be
composed of at least five members appointed
by the applicant and so selected that the
Committee will be competent to deal with the
medical. legal, social, and ethical issues in-
volved. At least one member of the Committee
shall be either a prisoner or a representative
of an organization having as a primary con-
cern protection of the interests of prisoners.
FEDERAL REGISTER, VOL. 38, NO. 221 — FRIDAY, NOVEMBER 16, 1973
31748
NOTICES
No more than one-third of the members may
be phyBlclans or scientists engaged In bio-
medical or behavioral research, and no more
than one member, other than a prisoners'
representative, may have any affiliation with
the prison facility or the legal entity having
Jurisdiction over the facility, except for per-
sons employed by a I>epartment of Education
In a teaching capacity. Any prisoners serving
on the Committee shall be compensated at a
rate consistent with that set for prisoners
participating as subjects In activities at the
facility to which this subpart Is applicable.
(c) The Protection Committee shall estab-
lish rules of procedure for conducting Its
activities which must be reviewed by DHEW.
and shall conduct Its activities at convened
meetings, minutes of which shall be prepared
and retained. The composition of the Com-
mittee shall be subject to DHEW approval.
Section 46 46 Prohibition on participa-
tion in activities prior to completion. No in-
dividual confined pending arraignment, trial,
or sentencing for an offense punishable as a
crime may be used as a subject In any ac-
tivity supported In whole or In part by a
grant or contract to which this subpart Is
applicable.
Section 46 47 Remuneration to subjects.
Where rates of remuneration are set pursu-
ant to 5 46-44 of this subpart, any subject
who, for medical reasons. Is required by a
representative of the prison facility, grantee,
contractor, or sponsor of the activity, to with-
draw before completion of his or her partici-
pation In the activity shall continue to be
compensated for a period to be set by the
Protection Committee after consultation with
the grantee or contractor
Section 46 48 Accreditation. It Is the In-
tention of DHEW to accredit prison facilities
as Bites for the performance of activities to
which this subpart applies. Accreditation
will be based on certification of the accepta-
bility of the facilities and compliance with
the procedures required by this subpart, as
determined by the Secretary. No activity
covered by this subpart may Involve prison-
ers incarcerated In a facility not accredited
by Secretary of DHEW,
Section 46 49 Activities to be performed
outside the United States. In addition to
satisfying all other applicable requirements
In this subpart, an activity to which this sub-
part Is applicable, which Is to be conducted
outside the United States, must include writ-
ten documentation satisfactory to DHEW
that the proposed activity is acceptable under
the legal, social, and ethical standards of the
locale In which It Is to be performed.
E— Add
I Men
Protections i
TALLY Infirm I
IN-
Section 46.51 Applicability, (a) The regu-
lations in this subpart are applicable to all
Department of Health, Education, and Wel-
fare activities involving the institutionalized
mentally Infirm as subjects.
(b) Nothing in this subpart shall be con-
strued as indicating that compliance with the
procedures set forth herein in connection
with activities permitted under § 46.54 of this
subpart will necessarily result in a legally
effective consent under applicable State or
local law to a subject's participation in such
an activity, nor In particular does it obviate
the need for court approval of such participa-
tion where court approval is required under
applicable State or local law In order to
obtain a legally effective consent
(c) The requirements of this subpart are
In addition to those imposed under Subparts
A, B, and D of this part.
Section 46 52 Purpose It is the purpose
of this subpart to provide additional safe-
guards Sot the mentally Infirm involved in
research, development, and demonstration,
activities. Inasmuch as the potential eubjects
in such activities are; (1) Confined In an
Institutional setting; (2) might be unable
fully to comprehend the type risks which
may be Involved: and (3) might be legally
Incompetent to consent to their participa-
tion )n BUch activities.
Section 46,53 Definitions As used In this
subpart:
(a) "DHEW activity" means:
( 1 ) The conduct or support ( through
grants, contracts, or other awards) of bio-
medical or behavioral research Involving
(2) Research, development, or demonstra-
tion activities regulated by any DHEW
agency.
(b) •■Mentally infirm" includes the men-
tally Ul. the mentally retarded, the emotion-
ally dlstiirbed. the psychotic, the senile, and
others with Impairments of a similar nature,
regardless of whether or not the Individual
has been determined to be legally
incompetent.
(cj "Institutionalized" means confined,
whether by court order or voluntary com-
mitment, in an Institution for the care and/
or treatment of the mentally infirm.
Section 46 54 Limitations on activities in-
volving the institutionalized mentally infirm.
No Institutionalized mentally mfirm indi-
vidual may be included as a subject in a
DHEW activity unless:
(a) The proposed activity Is concerned
with: (1) The diagnosis, treatment, preven-
tion, or etiology of the impairment with
which he or she Is afflicted; or (2) the pro-
posed activity is concerned with the effect
of institutional life on the subject and in-
volves no risk of harm to the subject; or
(3) the information caii be obtained only
from such subjects.
(bi The individual's legal guardian has
given consent to the Individual's particlpa-
uch i
vlty;
(c) Where the individual has sufficient
mental competency to understand what is
proposed and to express an opinion as to his
or her participation, tlie Indivldxial's con-
sent to such participation has also been
(dt The Protection Committee, provided
for In S 46 56 of this subpart, has reviewed
and approved subject participation In the
activity (by class or by Individual).
Section 46.55 Additional duties of Organ-
izational Review Committee where the men-
tally infirm are involved (a) In addition to
its re-sponsibillties under Subpart A of this
part, the Organizational Review Committee
shall, with respect to activities to which
subpart applies:
(1) Certify that all aspects of the activity
would be ethically appropriate for perform-
ance on healthy individuals:
(2) Conduct at least one on-site visit to
the institution and prepare a report of the
visit, including discxisslon of such matters
as living conditions, availability of medical
care, and quality of food, to he submitted to
DHEW along with the application;
(31 Review and approve or modify the
procedures proposed by the applicant to be
followed by the Protection Committee, pro-
vided for in 5 46 56, In overseeing the re-
cruitment of the mentally infirm subjects
who may be hicluded in such activity;
(4) Recommend any additional functions
to be performed by the Protection Commit-
tee In connection with any particular ac-
tivity; and
(5) Carry out such other responsibilities
as may be recommended by DHEW.
(bl Activities to which this subpart Is ap-
plicable must provide for the designation of
an Organizational Review Committee where
no such Committee has been established
under subpart A.
Section 46 56 Protection Committees:
duties: composition, (al No activity covered
by this subpart will be approved unless it
provides for the establishment of a Protec-
tion Committee to carry out the following
functions, as well as any others prescribed
by the Organizational Review Committee or
by DHEW: (1) Overseeing the process of
selection of subjects who may be included
In the activity. (2) monitoring the progress
of the activity with special attention to
adverse effects on subjects, (3l lnter\enlng
on behalf of one or more of the subjects if
conditions warrant, (41 evaluating the proc-
ess and reasonableness of consent of the
legal guardian and (where applicable) of the
subject, and (5) advising the legal guardian
and or the subject concerning the latler'a
continued participation in the activity if
(b) The composition of each Protection
Committee shall conform to the require-
ments set forth In ! 4626(a).
(c) The Protection Committee shall es-
tablish rules of procedure for conducting Its
activities, which must be reviewed by DHEW,
and shall conduct its activities at convened
meetings, minutes of which shall be prepared
and retained.
Section 46,57 Activities to be performed
outside the United States. In addition to
satisfying all other applicable requirements
in this subpart, an activity to which this
subpart is applicable, which is to be con-
ducted outside the United States, must In-
clude written documentation satisfactory to
DHEW that the proposed activity is accept-
able under the legal, social, and ethical
standards of the locale in which It Is to be
performed.
Subpart F — Gen
Pbovisions
Section 46 61 Applicability. The following
regulations are applicable to all activities
covered by this part.
Section 46 62 Records, (a) Copies of all
documents presented or required for Initial
and continuing review by any Organizational
ReWew Committee or Protection Committee
and minutes, transmittals on actions. In-
structions, and conditions resulting from
committee deliberations are to be made part
of the official files of the grantee or con-
tractor for the supported activity.
(b) Records of subject's and representa-
tives consent shall be retained by the
grantee or contractor In accordance with Its
established practice, or. if no practice has
been establiehed. In project files.
(c) Acceptance of any DHEW grant or
contract award shall constitute consent of
the grantee or contracting organization to
inspection and audit of records pertaining to
the assisted activity by authorized repre-
sentatives of the Secretary.
(dl All documents and other records re-
qmred under this part must be retained by
the grantee or contracting organization for
a minimum of three years following termina-
tion of DHEW support of the activity.
Section 46 63 Reports. Each organization
with an approved aj^surance shall provide the
Secretary with such reports and other in-
formation as the Secretary may from time to
Section 46,64 Early termination of
awards: sanctions for noncompliance, (a)
If. in the Jxidgment of the Secretary*, an or-
ganization has failed to comply w*ith the
terms of this part with respect to a par-
ticular Federal activity, he may require that
said grant or contract be terminated or sus-
pended In the manner prescribed in appli-
cable grant or procurement regulations.
FEDERAL REGISTER, VOL 38, NO. 221 — FRIDAY, NOVEMBER 16, 1973
NOTICES 31749
(b) If. In the Judgment of the Secretary. (c) If. tn the Judgment of the Secretary. coutUme u\\t\l It Is shown to the satisfaction
an organization falls to discharge its re- an individual serving as principal Investi- of the Secretary that the reasons therefor no
sponsibiltties for the protection of the rights gator, program director, or other person hav- longer exist.
and welfare of the subjects In its care. Ing responsibility for the scientific and tech- Section 46.65 Conditions. The Secretary
Whether or not DHEW funds are Involved, he nlcal direction of a project or activity has ^i^h respect to any activity or any clas3
may. upon reasonable notice to the organiza- failed to discharge her or his responsibilities , ^, ., , _,^, , , _,
tion of the basis for such action, determine for the protection of Ihe rights and welfare °^ activities Impose conditions. Including
that its eligibility to receive further DHEW of human subjects in his or her care, the conditions pertaining to informed consent.
grants or contracts or participate tn DHEW Secretary may. upon reasonable notice to the prior to or at the time of the approval of
assisted activities. Involving human subjects. Individual of the basis for such action, deter- any activity when in the Secretary's Judg-
shall be terminated. Such disqualification mine that such Individual's eligibility to ^lent such conditions are necessary for the
shall contintie until it is shown to the satis- serve as a prmcipal Investigator or program t i r v, hit
faction of the Secretary that the reasons director or in another similar capacity shall protecLion oi numan subjects,
therefor no longer exist. be terminated. Such disqualification shall [PR Doc.73-23922 Filed U-16-73;8;45 am]
FEDERAL REGISTER, VOL 30, NO. 221— FRIDAY, NOVEMBER 16, 1973
21
PROTECTION OF HUMAN SUBJECTS:
PROPOSED POLICY
Federal Register, August 23, 1974, DHEW
FRIDAY, AUGUST 23, 1974
WASHINGTON, D.C.
Volume 39 ■ Number 165
PART III
DEPARTMENT OF
HEALTH,
EDUCATION, AND
WELFARE
Office of the Secretary
PROTECTION OF
HUMAN SUBJECTS
Proposed Policy
Jto. i«s— Pt. ni — 1
DEPARTMENT OF HEALTH,
EDUCATION, AND WELFARE
Office of the Secretary
[45 CFR Part 46)
PROTECTION OF HUMAN SUBJECTS
Proposed Policy
In the Federal Registeb of May 30
1974 (39 PR 18914), reeulatlons were
published as Part 46 of Title 45 of the
Code of Federal Regtilatlons providing
generally for the protection of human
subjects Involved in research, develop-
ment, or related activities supported by
Department grants or contracts. At that
time it was indicated that notices of
proposed rulemaking would be developed
concerning minors, fetuses, abortuses,
prisoners, and the Institutionalized men-
tally disabled.
Colncldentally with the development
of the notice of proposed rulemaking
set forth below, both Houses of Con-
gress reached agreement on the "Na-
tional Research Act." and the President
signed P.L. 93-348 into law. Among other
things, the Act establishes an eleven-
member National Commission for the
Protection of Human Subjects in Bio-
medical and Behavioral Research to
' • (1) conduct a comprehensive In-
vestigation and study to Identify the
basic ethical principles which should
underlie the conduct of biomedical and
behavioral research Involving human
subjects, (li) develop guidelines which
should be followed to such research to
assure that It Is conducted in accordance
with such principles, and (ill) make
recommendations to the Secretary (I)
for such administrative action as may
be appropriate to apply such guideline's
to biomedical and behavioral research
conducted or supported under programs
administered by the Secretary, and (H)
concerning any other matter pertaining
to the protection of human subjects of
biomedical and behavioral research "
This notice of proposed rulemaking is
published today to contmue the public
dialogue begun in November 1973 when
the Director of the National Institutes
of Health published draft proposals on
these Issues in the Federal REcisreR. The
comments addressed In tills preamble are
the result of that issuance.
The comments received as a result of
this notice of proposed rulemaking wlU
not only assist the Department to de-
velop final regulations but will also be
available to the Commission for their use
during the course of their deliberations
over the next two years.
In the light of the 450 responses re-
ceived as a result of the November issu-
ance, largely from grantee and contrac-
tor organizations, the Department now
proposes that, in addition to the protec-
tion afforded generally to all subjects of
research, development, and related ac-
tivities supported by the Department by
virtue of Part 46, further protective
measures should be provided for those
subjects of research whose capability of
providing Informed consent Is or may be
absent or limited.
PROPOSED RULES
This would be accomiJlished by amend-
ing Part 46 to delete 5 46.19 through
46 22, redesignating 5 46.1 through 46.18
as Subpart A. and adding new Subparts
B tlirough P. If this proposal is accepted,
the regulations would be structured as
follows;
Subpart A would be the basic regula-
tion, substantially as promulgated on
May 30. 1974. This provides that no activ-
ity involving any human .subject at risk
shall be supported by a DHEW grant or
contract unless the applicant or offering
organization has established an organi-
zational review committee which has re-
viewed and approved such activity and
submitted to DHEW a certification of
such review and approval. This subpart
also provides that all grant and contract
proposals involving human subjects at
risk are to be additionally evaluated by
the Secretary for compliance with the
requirements of said subpart.
Subpart B is reserved for a separate,
future proposed rulemaking providing
additional protection for children.
Subpart C as described In the present
proposed rulemaking would call for the
utilization of two special mechanisms
for the protection of the pregnant woman
and unborn child or fetus, where the
pregnant woman participates in a re-
search, development, or related activity.
While these mechanisms are designed to
allow sufficient flexibility for the pursuit
of new information about the perinatal
process, they are also designed to provide
additional safeguards to assure that the
research is acceptable from an ethical
standpoint.
Subpart D as described In the present
proposed rulemaking would give added
responsibilities to an organizational re-
view committee where the contemplated
research would Involve prisoners as sub-
jects and also would require In such in-
stances that a consent committee be es-
tablished to supervise the selection and
participation of prisoners in the re-
search. Prisoner groups are particularly
valuable in properly conducted clinical
trials since they provide a stable subject
population which can be followed over a
period of weeks or months rather than
days or hours. From the point of view of
the prisoner subject, participation in re-
search offers an opportunity to make a
contribution to society and to provide an
income, much as other jobs in prison do
Nevertheless, the dangers of abuse of
prisoners' rights are obvious. For this
reason, the proposed rulemaking calls
for additional safeguards for the rights
of prisoners whose capability to provide
Informed consent may be affected by the
very fact of their Incarceration.
Subpart E as described in the present
proposed rulemakmg offers additional
protections for the rights of the mentally
111, the mentaUy retarded, the emotion-
ally disturbed, and the senile who are
confined to institutions, whether by vol-
untary or Involuntary commitment Such
persons, by the very nature of their dis-
abUities, may be severely limited In their
capacity to provide Informed consent to
their participation in research. At the
same time, the nature of their disabili-
ties requires extensive research efforts
to the study of the etiologj'. pathogenesis,
and therapy of their conditions. The pro-
posed rulemaking limits the research in
which such subjects may be allowed to
participate to that which is most likely
to be of assistance to them or to persons
similarly disabled.
In developing the present proposed
rulemaking, the Department has taken
Into consideration the public's comments
relevant to certain parts of the Introduc-
tion, Definition, and General Policy Sec-
tions of the draft regulations published
at 39 FR 18914, November 16. 1973. as
well as to the draft regulations them-
selves. The major comments, and the De-
partment's present proposals, are as
follows:
Introduction, General Policy
Considerations
A. Commentators suggested, in several
different contexts, that the regulations
should (1) apply to all research, regard-
less of the degree of risk or academic dis-
cipline concerned, and (ID provide for
the exclusion of certain types of research,
particularly behavioral and social science
research as distinguished from biomedi-
cal research.
The Department, having considered
these comments, notes that the appllca-
blllty provisions of the basic regulations
(45 CFR 46.1) permit the Secretary to
determine whether specific programs
place subjects at risk. Such determina-
tion Is to be made only after careful study
and publication in the Federal Register.
providing an opportunity for comment on
the merits of each determination. With
respect to research in the social sciences,
the Department has already indicated
Its Intention of Issuing public rulemaking
on this matter (see 39 FR 18914, para-
graph A) .
B. Comments also included suggestions
Ql,^t regulations should be proposed spe-
cifically dealing with activities Involv-
ing students, latwratory employees,
seriously 111 or terminal patients, the non-
institutionalized mentally disabled, and
other special groups.
The Department considers that any
abuses relating to these groups are less
evident and that they are afforded the
protection of the existing regulations
published In 39 PR 18914.
C. Several comments suggested the
provision of additional guldeUnes with
respect to the distinction between estab-
lished and accepted methods on the one
hand and experimental procedures on the
other.
While the Department recognizes the
theoretical desirability of such guide-
lines, and that the practical necessity of
making such a distinction is arising with
Increasing frequency, the feasibility of
making this distinction on a generalized
basis has yet to be demonstrated. At the
moment a regulatory approach to this
Issue does not appear Justified.
D. It was suggested that all meetings
of organisational review committees and
similar groups established pursuant to
FEOERAl REGISTER, VOL. 39, NO. 165— FRIDAr, AUGUST 23. 1974
PROPOSED RULES
1^0649
these regulations should be open to the
pubhc.
The Department notes that since the
puipose of these committees is, for the
most part, to advise with respect to the
conduct of individual projects and pro-
posals by individual investigators, a
blanket provision to 'this effect would
appear to be inconsistent with the need
to protect the confidentiality of the pro-
ceedings and records of institutional re-
view and evaluation committees.
Definitions
A. Comments on the definition of
"Subject at Risk" suggested changes in
language that would (i) limit the con-
cept of risk to that encountered only in
addition to that normally experienced,
(ii) eliminate demonstration projects as
a possible source of risk, since these are
nominally limited to application of estab-
lished and accepted methods, (iii) spe-
cifically identify failure to maintain con-
fidentiality as a source of risk, and (iv>
provide a mechanism for identifying ac-
tivities essentially free of risk.
These comments are similar to those
made with respect to the same definition
as incorporated in an earlier proposed
rulemaking (38 FR 27882). In respond-
ing to the criticism, the Department has
already (i) redefined "Subject at Risk"
in 45 CFR 46.3 'b) so as to exclude any
axitivlty which does not increase the
ordinary risks of daily life or the recog-
nized risks inherent in a chosen occupa-
tion or field of service. *ii) substituted
in 45 CFR 46. Ha) the term "develop-
ment" for "demonstration," *iii) pro-
vided in 45 CFR 46.19 'b) specific
prohibitions against disclosures of infor-
mation which refers to or can be identi-
fied with a particular subject, and (iv)
provided in 45 CFR 46.1(b) authority
for determination in advance as to
whether a particular Federal program
or an investigational method or proce-
dure may place subjects at risk.
B. Comments on the definition of
"Clinical Research" suggested inclusion
in said definition of the behavioral as-
pects of research and facets of medical
research necessarily concerned with
diagnosis and other nonetherapeutic
aspects of research.
Since the term "clinical research"
does not occur in the present rulemak-
ing, the Department reserves its opinion
with respect to these suggestions. How-
ever, the proposed regulations are appli-
cable to all departmental research, devel-
opment, and related activities except
with respect to Subpart C, where appli-
cability is limited to "biomedical
research" t§ 46.303(b) >.
C. Comments on "Informed Consent"
suggested the addition of language con-
cerning (i) full and complete disclosure,
(ii) the likelihood of success or failure
of the experiment, (iii) the use of place-
bos or other control procedures, liv)
provision of information as to the prog-
ress of the research, (v) publication of
names of all persons, institutions, and
review committees involved in approval
of consent procedures, (vi) provision of
legal counsel and technical advice, and
(vii) assurance that the subject com-
prehends the disclosure.
The Department, having considered
these comments, notes that "Informed
Consent" is presently defined in 45 CFR
46,3(c) and not in the present proposed
rulemaking. With respect to the specific
suggestions the Department notes that:
as far as (i) is concerned, the reg-
ulations already call for a "fair explana-
tion" of the procedures and a description
of risks and benefits reasonably to be
expected; (ii) refiects a basic misunder-
standing of the experimental process
which begins, essentially, with the com-
parison of two or more methods, proce-
dures, or modalities on the a priori
hypothesis that there wall be no differ-
ence; (iii) is implicit in the existing regu-
lations and is better emphasized in inter-
pretive materials; (iv) would not be an
element of informed consent unless in-
terim findings affected the risk of benefit
involved; and (v) touches on the subject
of a possible future proposed rulemaking
and the Department resen'es its options
for the present. The suggestion in (vi)
is met in part by the proposals in the
present proposed rulemaking to employ
consent committees to advise potential
subjects. The last suggestion (vii) goes
beyond requirements for informed con-
sent as they have generally been articu-
lated by the courts.
D. Comments also included sugges-
tions for the inclusion of additional defi-
nitions of (i) Institutions, (ii) Legal
Guardian, (iii) Organizational Review
Committee, (iv) Institutionalized Men-
tally Infinn. and (v) Children (with re-
gard to age of consent), Parents, and
Father.
The Department, having reviewed
the.se comments, notes that (i) "Organi-
zation" is defined for the purpose of
these regulations to include "institu-
tions" at 45 CFR 46-3(a>; (iii ■'Legally
authorized representative" is defined for
the pui'pose of these regualtions to in-
clude legal guardian at 45 CFR 46.3(h) ;
(iii) the definition of "organizational re-
view committee" is implicit in 45 CFR
46.6; (iv) ""Institutionalized mentally
disabled" has been defined in the pres-
ent proposed rulemaking at 46.503(d)
to meet the suggestion; and (v) defini-
tion of "Children." "Parents." and
"Father" will be reconsidered prior to
the issuance of a future rulemaking cov-
ering research on children.
E. Several commentators criticized
provisions of the draft policy that would
have required that activities to be con-
ducted outside the United States satisfy
all requirements of the Departments reg-
ulations including those based on ethical
concepts peculiar to the Judeo-Christian
moral heritage or to English common
law. It was noted that this would create
substantial problems for United States
investigators working overseas since
these concepts are often inconsistent if
not in conflict with normal, ethical, and
legal concepts in certain foreign coun-
tries. For the same reasons, it was argued
that these provisions would create prob-
lems for United States citizens assigned,
detailed, seconded, or acting as consult-
ants to international organizations or to
foreign governmental or private insti-
tutions.
Having considered these objections, the
Department proposes to retain the basic
concept that activities supported by De-
partmental funds should, m general, be
subject to a uniform etliical policy
wherever they are conducted, but to per-
mit the Secretary to modify consent pro-
cedures if it can be demonstrated to his
satisfaction that such procedui'es. as
modified, are acceptable under the legal,
social, and ethical standards of the locale
in which the activities are to be
performed.
Since comments on the draft provi-
sions in 38 CFR 31738 providing addi-
tional protections for fetuses, abortuses.
in vitro fertilization, and pregnant wom-
en were integrated with those on chil-
dren, it is difficult to identify the com-
munications specifically concerned with
these subjects. However, it is estimated
that the majority of the more than 400
letters received on research with chil-
dren, born and unbora. touched on one
or more aspects of research with fetuses,
abortuses, and pregnant women.
A. A large number of respondents dis-
agreed entirely with the idea of permit-
ting research with the fetus, with the
abortus (whether living or dead) , or with
the pregnant woman if the research
might conceivably endanger the fetus.
The Department, having carefully con-
sidered these comments and similar pro-
posals reflected in general corre.spond-
ence and in articles in the public media,
notes that their adoption would seriously
hamper the development of needed im-
provements in the health care of the
pregnant woman, the fetus, and the new-
born. The opposition to research involve-
ment of the fetus and abortus appears
to be based in part on the assumption
that the needed infonnation can be ob-
tained through research with animal spe-
cies or with adults. Unfortunately, these
assumptions are not valid. While mucii,
useful research can be conducted in ani-
mals, differences in species are neverthe-
less so great that any research finding
in nonhuman species must ultimately be
repeated in man before its general ap-
plication in human m_edicine. In addi-
tion, the fetus and the newborn are not
small adults. They suffer from some dis-
eases not encountered m the adult. Tliey
may react differently to the diseases
commonly affecting both adult and
young, and they may have a different
response to the same treatment, both
with regard to its effectiveness and to
its safety. The Department therefore
proposes that n> the ethical probity of
any appliration or proposal for the sup-
port of any activity covered by subpart
C be reviewed by an Ethical Advisory
Board as described in §46.304. and 'li)
the conduct of any such activity sup-
ported by the Department be subject to
oversight and monitoring by a consent
committee as described in § 46.305.
FEDERAL REGISTER, VOL. 39, NO. 165 — FRIDAY, AUGUST 23, 1974
30650
B. Opinion was divided as to the need
for an Ethical Advisory Board. Many
respondents called It a welcome addi-
tion In the review process. Others felt
that It would duplicate the function of
the local organizational review committee
and that Its existence would encourage
the organizational review committee to
be less critical and would Impose an addi-
tional roadblock that would delay or pro-
hibit Important research while needlessly
consuming time, energy, and money, and
posing potential danger to a patient wait-
ing for treatment. Complaints were
voiced that such decisions should be made
locally, not In Washington, and that the
Investigator should be able to present
his case In person. Numerous comments
suggested that the Board's function
should be limited to advising on policy,
guidelines, or procedures, and not be
concerned ^ith the review of Individual
projects. This would avoid duplicating
the function of the organizational review
committee. Others suggested that the
Ethical Advisory Board should serve as
an appeal body from the organizational
review committee.
There were also numerous comments
to the effect that It Is unwise and Im-
possible to totally separate ethical and
scientific review. Approval based only on
ethics would be unethical if the science
were bad. Both should be reviewed
jointly.
The Department, having reviewed
these comments, concludes that Ethical
Advisory Board remains. In concept, a
useful addition to the review pi-ocess. It
does not uuplicate the functions of the
local organizational review committee,
since the latter Is primarily concerned
with matters of organizational regula-
tions, local standards of professional
practice, applicable law within its Juris-
diction, and local community attitudes.
The Ethical Advisory Board will be pri-
marily concerned with similar issues at
the national level, Apphcations and pro-
posals should be capable of passing
scrutiny at both levels. It is therefore
proposed that the Ethical Advisory Board
be retained as part of the additional
protection mechanism.
Specific comments regarding the
establishment of an Ethical Advisory
Board touched principally on di the pos-
sibility tliat appointment of members
at an agency level might lead to "loaded"
Boards, while appointment at a higher
level, i.e., by a Joint Congressional com-
mittee or by Independent outside bodies,
might produce a more objective group,
and (ii> disagreement as to the proper
balance between scientist and nonsclen-
tist members, with a majority of the
commentators suggesting that more than
one-third of the members should have
the scientific expertise necessary to
identify risks and their possible conse-
quences. It was specifically suggested that
different sizes, compositions, and admin-
istrative locations of the Board be tried
before selecting a final mechanism. In
addition, it was suggested (ill) that a
fifteen member Board was too large, (Iv)
that all members be human geneticists,
<v) that at least one member be a psy-
PROPOSED RULES
chologlst. If behavioral Issues were to be
considered, fvi> that there be an absolute
ban on departmental agency employees.
(vU) that all proceedings be confidential,
(viil) that all meetings be open to the
public, and <lx) that an appeal mecha-
nism be established.
The Department, having considered
these views, proposes that while an Eth-
ical Advisory Board to deal with bio-
medical research Involving fetuses,
abortuses, pregnant women, and in vitro
fertilization might logically be estab-
lished at the National Institutes of
Health. (1) the power of appointment
should be reseiwed to the Secretary. (11)
while the membership should include re-
search scientists, physicians, lawyers,
clergy or ethlcists, and representatives of
the general public, the balance between
callings should rest with the Secretary
.as should also <iil) the number of mem-
bers, so that the membership (iv, vi can
be adjusted to the needs of the Board
as the workload and the Issues before it
dictate. The specific suggestion (see vi)
that departmental agency employees be
excluded is adopted and expande(l to In-
clude all full-time employees of the Fed-
eral Government. The decisions with re-
gard to suggestions (vll) and (vill) will
be governed by the provisions of the
Federal Advisory Committee Act which
generally require that meetings of simi-
lar advisory groups be open to the public
for the purposes of policy discussion, but
closed and confidential for the purpose
of review of specific applications and
proposals. Since the Board will be ad-
visory to funding agencies, the final ac-
tion will be that of existing awarding
authorities, and appeal mechanisms (ix)
will be provided only to the extent avail-
able under other existing departmental
regulations and policies. These proposals
are Incorporated into § 46.304.
C. A number of respondents recom-
mended that the policy governing in
vitro fertilization be strengthened, on the
one hand, or liberalized, on the other. The
Department has considered these recom-
mendations, and has provisionally chosen
not to stipulate at this time protec-
tions for the product of in vitro fertiliza-
tion which is not implanted, but rather
to leave that series of issues to the Ethi-
cal Advisory Board established under
§ 46.304(a). The Board will be required
to weigh, with respect to specific re-
search proposals, the state of the art.
legal issues, community standards, and
the availability of guidelines to govern
each research situation.
Because biomedical research is not yet
near the point of being able to maintain
for a substantial period the non-
implanted product of in vitro fertiliza-
tion, no clear and present danger arises
from not stipulating in these regulations
the protections tor it. Given the state of
the research, we believe that such stipu-
lation would be premature.
It is the Department's Intent that the
definition of the term "fetus" (5 46.303
(d) ) be construed to encompass both
the product of in vivo conception and
the product of in vitro fertilization which
Is subsequently Implanted in the donor
of the ovum. 'Whatever the nature of the
conception process, it is Intended that
upon implantation the protections of
subpart C apply to all fetuses. It Is only
with respect to the protections available
to the non-implanted product of in
vitro fertilization that the regulations
are silent.
With respect to the fertilization of
human ova in vitro, it is expected that
the Board will consider the extent to
which current technology permits the
continued development of such ova. as
well as the legal and ethical Issues sur-
rounding the Initiation and disposition
of the products of such research.
With respect to Implantation of fer-
tilized human ova. it Is expected that
the Board will consider such factors as
the safety of the technique (with respect
to offspring) as demonstrated in animal
studies, and clarification of the legal
responsibilities of the donor and recipi-
ent parent(s) as well as the research
personnel.
Since the Department does reserve
the option of later specifying such pro-
tections by regulation, we invite com-
ment on the question of appropriate
regulations in the future.
D. The draft proposals Included a
suggestion for the establisiiment of a
protection committee which elicited nu-
merous comments that the use of the
term "protection committee" Implies that
the Department recognizes a clear, pres-
ent need for protection against the In-
vestigator, the uncertain relation of this
committee to the organizational review
committee, and the uniform need for
and desirability for such protection.
Having reviewed these comments, the
Department proposes an extensive revi-
sion in this Innovative concept. Initially,
it acknowledges that the term "protec-
tion committee" is pejorative and pro-
poses the term "consent committee" as
more appropriate and consistent with
the primary purpose of such bodies. Fur-
ther, it proposes to eliminate specific re-
quirements for the size and composition
of such committees. Instead, applicants
and offerors are to propose the estab-
lishment of such a committee, specifying
its size, composition, and rules of proce-
dure. In addition, where the applicant
or offeror believes that the activity in-
volves only negligible risks, it may ask
the Secretary to waive or modify the re-
quirement for a consent committee. All
proposals for the establishment, modi-
fication, or waiver of a consent commit-
tee shall be subject to review and
approval at the local level by the or-
ganizational review committee and at
the departmental level by the Ethical
Advisory Board. The Ethical Advisory
Board may prescribe additional duties
for the consent committee. These
changes are incorporated in § 46.305. In
view of this drastic change In concept
of the committee, detailed discussion of
the many excellent and often thought-
provoking comments concerned with
details of the original draft seems
inappropriate.
fEDERAl RiGISTEH, VOL. 39, NO. 165— FRIDAY, AUGUST 23, 1974
PROPOSED RULES
30651
E. Many critical comments were ad-
dressed to the definitions used in this
subpart, specifically:
1. "Pregnancy." It was suggested that
pregnancy should be defined (i' con-
ceptually to begin at the time of fertil-
ization of the ovum, and (iii operation-
ally by actual test unless the woman has
been surgically rendered incapable of
pregnancy.
While the Department has no argu-
ment with the conceptual definition as
proposed above, it sees no way of basing
regulations on the concept. Rather, in
order to provide an administerable pol-
icy, the definition must be based on
existing medical technology which per-
mits confirmation of pregnancy. This
approach is reflected by § 46.303(c>.
2. "Viability of the Fetus". Many rec-
ommendations were received concerning
the definition of viability of the fetus
after premature delivery or abortion.
Some respondents urged that presence
of fetal heartbeat be definitive (whether
or not there is respiration) while others
ui'ged that identifiable cortical activity
be specified as an alternative sign of
viability. The Department has concluded
that the issue of viability is a fimction
of technological advance, and therefore
must be decided with reference to the
medical realities of the present time. We
reserve the option of redefining the pa-
rameters as conditions warrant.
Only uiton the basis of a definition
which is both precise and consistent with
current medical capability can a regula-
tion realistically be interpreted and en-
forced. Current technology is such that
a fetus, given the benefit of available
medical therapy, cannot survive unless
the lungs can be inflated so that respira-
tion can take place. Without this capa-
bility, even if the heart is beating, the
fetus is nonviable. In the future, if tech-
nology has advanced to the point of sus-
taining a fetus with non-inflatable lungs.
the definition can and should be modified.
The Department has therefore chosen
to specify, in the definition of viability
of the fetus (§ 46.303(e) ) , that heart
beat and respiration are. jointly, to be
the indicator of viability.
3. "Abortus." Various comments noted
that this definition is more restrictive
than the usual medical definition of the
abortus as a "nonviable fetus," and sug-
gested substitution of the broader
definition.
The Department proposes to retain the
original definition for the purposes of
these regulations. There is general agree-
ment that there are distinct ethical prob-
lems involved in decisions concerning
research use of the intact fetus, or use
of organs or tissues obtained from a fetus
that has died in utero or from an abortus
at autopsy. The definition recurs with
minor editorial changes in § 46.303(f).
F. Several comments were critical of
the draft regulation's provisions limiting
activities involving pregnant women to
those not adversely affecting the fetus,
except where the primary purpose of the
activity was to benefit the fetus. It was
suggested that the regulations (i) should
contain language permitting exceptions
for research necessary to meet the health
needs of the mother, and (ii) should
grant the right to participate in research
aimed at improvement of methods of
abortion, birth control, and genetic
mtervention.
The Department concms with the first
suggestion, (it, and proposes that the
regulations permit research whose pri-
mary interest is to benefit the particular
fetus or to respond to the health needs
of the pregnant A'oman, It does not fully
accept the second suggestion. (ii>, and
proposes that the regulations permit
fetal research concerned with diagnosis
and prevention of perinatal disease, and
to offset the effects of genetic abnormal-
ity or congenital injury, but only when
such research is done as part of a pro-
cedure properly pe.'"formed to terminate
a pregnancy. These changes are incor-
porated Into §46.306(a>. The Depart-
ment has tentatively concluded that
consideration of risk vs. benefit with re-
spect to fetal research does not seem to
be appropriate.
G. Draft regulation provisions re-
quired maternal consent and the consent
of the father if he were available and
capable of participating in the consent
process. This provision was strongly
criticized on the grounds that it could
permit the father of the fetus to deny
needed health care to the woman or to
the fetus even though he had no marital
obligations, and that it might result in
undue delay in the delivery of health
care. It was also pointed out that the
regulation did not touch on the question
of the validity of consent by a pregnant
minor.
The Department agrees. It is now pro-
posed that paternal consent be sought
only if the activity is not responding to
tlie health needs of the pregnant woman
and the father is reasonably available.
These changes are reflected by
g 46.306(b),
H. The Department has provisionally
chosen, in § 46.306Ca) , to permit research
to be undertaken from which there will
be risk of harm to the fetus if such
research is conducted as part of the abor-
tion procedure. This decision, upon
which we invite comment, has been made
in the expectation that such research
may produce new tecluiology which will
enable countless premature infants to
live who now cannot.
It is not intended that this provision
be construed to permit fetal research in
anticipation of abortion prior to the com-
mencement of the termination procedure
itself.
While it is true that the class of fetuses
for whom abortion is contemplated will
be placed at greater research risk than
all fetuses in general, such risk can arise
only after implementation of the double
safeguard of parental consent to the con-
templated abortion, and second parental
consent to the research procedure itself.
I. Comments regarding activities in-
volving the abortus were concerned with
the issue of maintaining vital functions
and signs. It was argued that maintain-
ing vital functions at the level of the
organ, tissue, or cell is essential to studies
and involves no prolongation of the dying
of the abortus. At the same time, It was
argued that termination of the heart beat
should not be prohibited since temporary
cardiac arrest has proved essential in the
development of surgical techniques nec-
essary to correct congenital heart defects.
Neither of these objections appear
valid and no significant changes in
5 46.307 are proposed. However, in order
to emphasize again the distinction be-
tween research with the whole fetus or
abortus, functioning as an organism with
detectable vital signs, and with the dead
fetus or abortus, the Department has
added i; 46.308. concerning activities in-
volving a dead fetus or abortus, and
§ 46.309, concerning the abortus as an
organ or tissue donor. Also § 46.307(d)
has been expanded to permit the artifi-
cial maintenance of vital functions of an
abortus where the purpose is to develop
new methods for enabling the abortus to
sui-vive to the point of viability.
The Department feels that there is evi-
dent distinction between "termination"
and "arrest" of the clinical signs as ap-
plied to the fetus or premature infant,
but that no such distinction is valid or
applicable where the abortus Is con-
cerned.
Prisoners
Forty-seven responses spoke to tlie pro-
visions regarding additional protection
for prisoners involved as subjects. Of
these, two were from individuals identi-
fying themselves as prisoners, seven
were from State correctional institutions
or State agencies, and four .^ere from
representatives of the pharmaceutical
industry.
A. In comments directed at the overall
nature of the draft regulations providing
additional protection for prisoners, ap-
proximately equal numbers of respond-
ents (i) denied that any significant addi-
tions were necessary, and liii proposed
either the exclusion of prisoners from
any research or experimentation not in-
tended for the personal benefit of a
prisoner, or highly restrictive regulations
to accomplish the same purpose.
The Department, having reviewed these
comments, has not been persuaded that
any change should be made In the initial
proposal.
B. A number of comments were con-
cerned with the relationship between the
existnig organizational review commit-
tees and the proposed Protection Com-
mittee. It was pointed out by several that.
as proposed, the two committees would
not only have overlapping functions and
authority but could operate independent-
ly of each other with conflicting direc-
tives and objectives that would not
practicably provide additional protec-
tion of prisoners used as subjects.
The Department, recognizing the im-
portance of preserving the authority of
the organizational review committee as
the primary institutional focus for the
implementation of the Department of
Health, Education, and Welfare regula-
tions, proposes to assign to the organiza-
tional review committee the additional
duties specified under § 46.404(a).
FEDERAL REGISTER, VOL. 39, NO. 165 — FRIDAY, AUGUST 23, 1974
30652
A committee auxiliary to the organiza-
tional review committee, now designated
the consent committee, will have the
character and responsibilities siieclfled In
s 46 406 In keeping with this modified
I'josltlon it should be noted that v hen the
organizational review committee deter-
mines that' an activity would involve no
risk or negligible risk to any prisoner
while serving as a subject, the orsaniza-
tlon may request the Secretary to con-
sider a modiflcation or waiver of the re-
quirement for a consent committee.
C. Comments on the proposed prohibi-
tion of research involvement of persons
awaiting arraignment, trial, or sentenc-
ing expressed doubts that these individ-
uals should be denied the benefits of in-
novative procedures, particularly those
concerned with sociological research.
The Department agrees that the uni-
form exclusion of any such person from
research should not be mandatory and
proposes to permit his participation in an
activity as a subject when the risk is
negligible and the Intent of the activity
is therapeutic for him or relates to the
nature of his confinement. This moaifi-
cation Is Incorporated into § 46,406.
D. The draft requirement for DHEW
accreditation of prison facilities as sites
for the performance of research, de-
velopment, and related activities involv-
ing prisoner subjects was severely criti-
cized, principally because of the jurisdic-
tional problems inherent In any attempt
to impose a Federal regulatory require-
ment on an autonomous State facility.
The Department concludes that this
draft proposal was Ill-advised. However.
In order to attain the objective on an
activity basis, certain specific prerequi-
sites tor the protection of prisoner sub-
jects within facilities have been added
to 5 46.404'a) to properly relate condi-
tions In a facility to the Issue of undue
Inducements to participation by pris-
oners as subjects In an activity.
Mentally Disabled
Over 40 of the responses spoke directly
to the section of the drart concerned with
the "mentally Infirm." Many of these ob-
jected Initially to the use of the word
"Infirm" as reflecting an antiquated
notion of mental illness.
The Department agrees, and proposes
to substitute "disabled" for "infirm,"
though noting that there Is no clearly
preferable collective term for the groups
described.
A. Comments on the purpose of this
section expressed satisfaction with the
Intent to provide additional protection
for this group but dissatisfaction with
the actual language employed. Specifi-
cally, they noted that not institutional-
ization but rather the limitation of per-
sonal rights and freedom Imposed by In-
stitutionalization Is the determining
issue. Similarly, it Is not only the poten-
tial subject's difficulty in comprehending
risks that is at issue, but his abihty to
comprehend generally.
The Department concurs. Proposed
changes in language are Incorporated In
5 46.52,
PROPOSED RULES
B. Many of the respondents objected
to one or more of the definitions peculiar
to this subpart. The criticisms and the
Deiiartment's proposed changes are as
fallows :
1. "Mentally infirm." In addition to
requesting substitution of another term
for "Infirm." respondents raised conflict-
ing objections to the definition's cover-
ase. .Some felt that It was overly in-
clusive: others felt it was too narrow.
Some felt that epileptics should be
.specifically included, as well as those who
are tcmixirarily or permanently mentally
incapacitated as a result of a physical
condition such as stroke, brain damage,
trauma, etc.
The Department, having carefully re-
viewed these comments, proposes no
basic change in the definition. It concurs
with many reviewers in the opinion that
the definition is broad enough to include
any category of subjects proposed for
specific addition. Minor editorial changes
have been made in §46, 503(b).
2, "Institutionalized," Commentators
noted that (i) the regulations should
cover all mentally disabled persons
regardless of institutionalization, 'ili not
all Involuntary commitments are by
order of a court, (ill) the draft refers to
"residence" and "confinement" in similar
contexts, though the terms do not carry
the same connotation, and (Iv) the de-
finition does not specify halfway houses,
lodges, day/night hospitals, nursing
homes, and psychiatric wards of hos-
pitals as places where subjects might be
institutionalized.
The Department notes that (1) the
non-institutionalized mentally disabled
are covered by the existing regulations
published as 39 FR 18914 and need not
be Included under these additional pro-
tections. Such individuals are not neces-
sarily subject to all limitations on their
freedom and rights as described in
§ 46-502 of tills proposed rulemaking.
Consideration will be given, however, to
dealing with the noninstltutionallzed
legally incompetent who are mentally
disabled In a subsequent notice of pro-
posed rulemaking. 'With regard to (ii).
the implication that court orders are
the sole basis for Involuntary confine-
ment is incorrect and should be removed.
Editorial changes have been made In
§ 46,503 to emphasize that concern there-
in Is with those "• • • confined • • •
in a residential Institution (see
ill) and, in order to designate the type
of Institutions concerned (see iv) , it is
proposed to separately define "Institu-
tionalized mentally disabled indiriduals"
in § 46,503 to include examples of such
Institutions. These changes are incor-
porated m 5 46, 503(c) and § 46, 503(d).
C, While most respondents endorsed
the Intent of the draft limitations on
activities involving the Institutionalized
mentally disabled, there were several
specific criticisms of the terms used.
Several persons suggested that any limi-
tation of research to that related to a
particular subject's "Impairment" be
worded so as to Include any Illness from
which the person suffer* so that, for ex-
ample, an In.-tltullonalizcd mentally dis-
abled person with cancer could not be
denied the benefits of research in cancer
therapy.
Further, this limitation could exclude
the u.se of such subjects a.s controls m
research which might benefit those
suffering from a mental disability other
than the specific one from which a
particular subject suffers. Still further,
mentally disabled people should be in-
volved as subjects Ui research on infirmi-
ties other than their own because of lack
of knowledge of the causes of menial and
emotional disorders.
Many respondents felt that there WTiS
inadequate recognition of the need for
research with the mentally disabled on
basic psychological processes (e,g,. learn-
ing, perception, and cognitive functions'
which are fun(3amental to the study of
the treatment, etiology, pathogenesis,
prevention. an(3 treatment of such dis-
abilities.
The Department agrees that the lan-
guage of the draft limiting research to
the disease entities affecting individual
subjects is probably not in the interests
of the institutionalized mentally disabled
as a class. The Department does not
agree that it would be appropriate to
permit this class of subjects to be in-
volved in research tinrelated to the
causes, nature, or circumstances of their
institutionalization. While there are
possible disadvantages to the institution-
alized mentally disabled inherent In this
restriction, the possible risks of using
the mentally disabled In such research
outweigh its advantages. The proposed
changes are incorporated in § 46.504"a).
Editorial changes are reflected in § 46.504
(b) and 5 46.504(c).
D. Criticisms of the draft's suggestion
of the establishment or a protection com-
mittee In cormection with each activity
conducted in an institution for the men-
tally retarded were similar to those aimed
at the protection committee to be estab-
lished in connection with research on the
pregnant woman and on the fetus. The
Department proposes to change the title
of the committee to "consent committee"
and to change the regulations governing
size, com^sitlon. and operating rules
to conform to those previously described
for § 46,305. Such changes are incorpo-
rated in § 46.506.
E, With respect, to i5 46.603ib). the
Department reserves the right to amend
this section if legislation now being de-
veloped by the Executive Branch on the
safe guarding of Individuallj' linked data
used for statistical and research purposes
is enacted.
Written comments concerning the pro-
posed regulation are invited from inter-
ested persons. Inquiries may be ad-
dressed and data, views, and arguments
relating to the proposed regulations may
be presented in writing, in triplicate, to
the Chief, Institutional Relations
Branch, Division of Research Grants,
National Institutes of Health. 9000 Rock-
ville Pike. Bethesda. Maryland 20014, All
comments received will be available for
Inspection at the National Institutes of
FEDERAL BECISTER, VOL, 39. NO 165 — FRIDAY, AUGUST J3, 1974
PROPOSED RULES
Health. Room 303. Wer-Lwooti Building.
5333 Westbard Avenue. Bethe^da. Mary-
land, weekdays i Federal holidays ex-
cepted) between the hours of 9:00 a,m.
and 4:30 p.m. All relevant material re-
ceived on or before November 21, 1974
will be considered.
Notice is also given that it is pro-
posed to make any amendments that are
adopted effective upon publication in the
Federal Register.
Dated: August 15. 1974.
Caspar W. Weinberger,
Secretary.
It is therefore proposed to amend Part
46 of Subtitle A of Title 45 of the Code
of Federal Regulations by :
1. Revising §§ 4619 through 46.22 and
renumbering them as §§46.603 through
46.606, reading as set forth in Subpart F
below.
2. Designating §§ 46.1 through 46.18 as
Subpart A, renumbering these §§46.101
through 46.118. and modifying all refer-
ences thereto accordingly.
3. Reserving Subpart B.
4. Adding the following new Subparts
C through F.
Pregnant Women, and In Vitro Fertiliz
46.301 AppUcablilty.
46.303 Purpose-
46.303 Deflntttons,
46.304 Ethical Advisory Board.
46.305 Establishment of a consent com-
mittee.
46.306 Activities Involving fetuses in utero
or pregnant women.
46.307 Activities involving abortuses.
46.308 Activities involving a dead fetus or
abortus.
46.309 Activities Involving the abortus as an
organ or tissue donor.
46.310 Activities to be performed outside
the United States.
46.401 -Applicability.
46.402 Purpose.
46.403 Definitions.
46.404 Additional duties of the organiza-
tlanal review committee where
prisoners are Involved,
46 405 Establishment of a consent commtt-
46.406 Special restrictions.
46.407 Activities to be performed outside the
United States.
tally Disabled as Subjects
46.501 Applicability.
46.502 Purpose.
46.503 Definitions.
46.504 Activities involving the Institution-
alized mentally disabled.
46.505 Additional duties of the organiza-
tional review committee where the
institutionalized mentally disabled
are Involved.
46.506 Establishment of a consent commlt-
Subpart F — General Provisions
46.601 Applicability.
>:nniiUee require
4G.''03 On
record;
itv.
46 G04 Repc.rU.
4G.C05 E.irly terminal
tiou of sulj5cquc?it applications.
4GG0G Condjlions
4C,G07 Artivities conducted by Dcpnrlment
AuriioriTV: 5 U,S,C- 301.
Subpart C — Additional PiotocfjorT? Pcriain-
ing to Biomedical Research, Develop-
ment, and Related Activities Involving
Fetuses, Abortuses, Pregnant Women,
and In Vitro Fertilinction
§ 46.301 .\i>plk:,hililv.
(a) The regulation,*^ in this subpart
are applicable to all Department of
Health, Education, and Welfare grants
and contracts supporting biomedical re-
search, development, and related activi-
ties involving: (1> the fetus in utero.
(2) the abortus, as that term is defined
in §46.303, (3) pregnant v/omen, and
(4) in vitro fertilization. In addition,
these regulations are applicable to all
such activities involving women who
could become pregnant, except where
the applicant or offeror shows to the
satisfaction of the Secretai-y that ade-
quate steps will be taken in the conduct
of the activity to avoid involvement of
women who are pregnant.
(b) Nothing in this subpart shall be
constmed as indicating that compliance
with the procedures set forth herein will
in any way render inapplicable pertinent
State or local laws bearing upon activi-
ties covered by this subpart,
(c> The requirements of this subpart
are in addition to tliose imposed under
the other subparts of this part.
§ 46.302 Purpose.
It Is the purpose of this subpart to pro-
vide additional safeguards in reviewing
activities to which this subpart Is appli-
cable to assure that they conform to ap-
propriate ethical standards and relate to
important societal needs.
§ 46.303 Definitions.
As used in this subpart:
(a) "Secretary" means the Secretary
of Health, Education, and Welfare or
any other officer or employee of the De-
partment of Health. Education, and
Welfare to whom authority has been
delegated-
(b) "Biomedical research, develop-
ment, and related activities" means re-
search, development, or related activi-
ties involving biological study (including
but not limited to medical or surgical
procedures, withdrawal or removal of
body tissue or fluid, administration of
chemical sub.stances or input of energy,
deviation from normal diet or hygiene,
and manipulation or observation of
bodily processes).
t c ) "Pregnancy " encompasses the
period of time from confinnation of im-
plantation until delivery.
(d) "Fetus" means the product of
conception from the time of implanta-
tion to the time of delivei-y.
(e) "Viability of the fetus" means the
abJlily of Uio fcl'.i^. r;fl':?r cither spon-
taneous or induced delivery, to survive
(given the bciV:'nt of available medical
therapy) to tlie jioint of independently
maintaining heai't beat and respiration.
If the fetus has this ability, it is viable
and therefore a premature infant.
(f 1 "Abortus" means a fetus when it Is
expelled w hoi?, prior to viability, whether
.■^pontcineously or as a result of medical
or .surpical intervention. The term does
not apply to tlie placenta: fetal material
which is macerated at the time of expul-
sion; or cells, tissue, or organs excised
from a dead fetus.
iR) "In vitro fertilization" means any
fertilization of human ova which occurs
outside the body of a female, either
through admixture of donor sperm and
ova or by any other means.
S 46.304 Eihiinl .\dwsory BoarJ.
<a) All applications or proposals for
the support of activities covered by
this subpart sliall be reviewed by an
Ethical Advisory Board, established by
the Secretary within the National In-
stitutes of Health, which shall advise
the funding agency concerning the ac-
ceptability of such activities from an
ethical standpoint.
tb) Members of the Board shall be so
selected that the Board will be compe-
tent to deal with medical, legal, social,
and ethical Issues and shall include, for
example, research scientists, physicians,
lawyers, and clergy and/or ethlclsts, as
well as representatives of the general
public. No Board member may be a reg-
ular, full-time employee of the Federal
Government.
(a> Except as provided in paragraph
Cc) of this section, no activity covered
by this subpart may be supported unless
the applicant or offeror has provided an
assurance acceptable to the Secretary
that it will establish a consent commit-
tee (as provided for in the application
or offer and approved by the Secretary)
for each such activity, to oversee the
actual process by which individual
consents required by this subpart are
secured, to monitor the progress of the
activity and intervene as necessary, and
to carry out such other duties as the
Secretary (with the advice of the Ethi-
cal Advisory Board) may prescribe. The
duties of the consent committee may
include:
(1) Participation in the actual selec-
tion process and securing of consents to
assure that all elements of a legally
effective informed consent, as outlined
in § 46.3, are satisfied. Depending on
what may be prescribed in the applica-
tion or offer approved by the Secretary,
this might require approval by the com-
mittee of individual participation in the
activity or It might simply call for veri-
fication (e.g.. through sampling) that
procedures prescribed in the approved
application or offer are being followed.
(2) Monitoring the progress of the ac-
tivity. Depending on what may be pre-
scribed In the application or offer ap-
proved by the Secretary, this might
FEDERAL REGISTER, VOL 39, NO. 165 — FRIDAY, AUGUST 23, 1974
30654
PROPOSED RULES
Include: visits to the activity site. Iden-
tlilcatlon of one or more committee
members who would be available for
consultation with those Involved In the
consent procedure (I.e.. participants) at
the participant's request, continuing
evaluation to determine If any unan-
ticipated risks have arisen and that any
such risks are communicated to the
participants, periodic contact with the
participants to ascertain whether they
remain willing to continue In the activ-
ity, providing for the withdrawal of any
participants who wish to do so. and au-
thority to terminate participation of one
or more participants with or without
their consent where conditions warrant.
(b) The size and composition of the
consent committee must be approved by
the Secretary, taking Into account such
factors as: (1) the scope and nature of
the activity: <2) the particular subject
groups involved; (3) whether the mem-
bership has been so selected as to be com-
petent to deal with the medical, legal,
social, and ethical issues Involved In the
activity; (4) whether the committee In-
cludes sufficient members who are un-
affiliated with the appUcant or offeror
apart from membership on the commit-
tee; and (5) whether the committee in-
cludes sufficient members who are not
engaged In research, development, or
related activities involving human sub-
jects. The committee shall establish rules
of procedure for carrying out its func-
tions and shall conduct its business at
convened meetings, with one of the mem-
bers designated as chairperson.
(c> Where a particular activity, in-
volving fetuses in utero or pregnant
women, presents negligible risk to the
fetus, an applicant or offeror may request
the Secretary to modify or waive the re-
quirement in paragraph (a) of this sec-
tion. If the Secretary finds that the risk
is indeed negligible and other adequate
controls are provided, he may (with the
advice of the Ethical Advisory Board i
grant the request in while or In part.
(dl The requirements of this section
and § 46.304 do not obviate the need for
review and approval of the application
or offer by the organizational review
committee, to the extent required under
Subpart A of this part.
§ 46,306 Aclivilirs involving fcluioa in
ulcro or pregnunt women.
(a I No activity to which this subpart
is apphcable, involving fetuses in utero
or pregnant women, may be undertaken
unless: (H the purpose of the activity is
to benefit the particular fetus or to re-
spond to the health needs of the mother,
or (2) the activity conducted as part of
(but not prior to the commencment of)
a procedure to terminate the pregnancy
and is for the purpose of evaluating or
Improving methods of prenatal diagnosis,
methods of prevention of premature
birth, or methods of intervention to off-
set the effects of genetic abnormality or
congenital injury.
(b) Activities covered by this subpart
which are permissible under paragraph
(a) of this section may be conducted
only if the mother and father are legally
competent and have given their consent.
except tliat the father's consent need
not be secured if: (1) the purpose of the
activity is to respond to the health needs
of the mother or (2) his identity or
whereabouts cannot reasonably be
ascertained,
(c) Activities covered by this subpart
which aj-e permissible under paragraph
(a) (2 1 of this section may not be under-
taken unless individuals engaged in the
research will have no part in: (1> any
decisions as to the timing, method, or
procedures used to terminate the preg-
nancy, and (2) determining the viability
of the fetus at the termination of the
pregnancy.
§ 46.307 Aclivilies involving aborlnsos.
No activity to which this subpart is
applicable, involving an abortus, may be
undertaken unless:
(a) Appropriate studies on animals
have been completed ;
(b) The mother and father are legally
competent and have given their consent,
except that the father's consent need not
be secured if his Identity or whereabouts
cannot reasonably be ascertained ;
(c) Individuals engaged in the re-
search will have no part in: (1) any de-
cisions as to the timing, method, or pro-
cedures used to terminate the pregnancy,
and (2) determining the viability of the
fetus at the termination of the preg-
nancy;
(d) Vital functions of an abortus will
not be artificially maintained except
where the purpose of the activity Is to
develop new methods for enabling the
abortus to survive to the point of viabil-
ity; and
(e) Experimental procedures which
would terminate the heart beat or res-
piration of the abortus will not be em-
ployed.
Activities involving a dead fetus or
abortus shall be conducted in accordance
with any applicable State or local laws
governing autopsy.
§ 46.309 .\i:livitics involving tlic aborliis
us an organ or tissue donor.
Activities involving the abortus as an
organ or tissue donor shall be conducted
in accordance with any applicable State
or local laws governing transplantation
or anatomical gifts.
Activities to which this subpart is ap-
plicable, to be conducted outside the
United States, are subject to the require-
ments of this subpart, except that the
consent procedures specified herein may
be modified if it is shown to the satis-
faction of the Secretary that such pro-
cedures, as modified, are acceptable
under the laws and regulations of the
country in which the activities are to be
performed and that they comply with
the requirements of Subpart A of this
part.
Subpart D- /'dditlonal Protections Pertain-
ing to Activities Involving Prisoners as
Subjects
§46.101 Api.li<ul>ilil>.
<a' The regulations in this subpart
are applicable to all Department of
Health, Education, and Welfare grants
and contracts supporting research, de-
velopment, and related activities involv-
ing prisoners as subjects.
'b) The requirements of this subpart
are in addition to those imposed under
the other subparts of this part.
§ 46.402 Purpose.
It is the purpose of this subpart to pro-
vide additional safeguards for the pro-
tection of prisoners Involved in activities
to which this subpart is applicable, inas-
much as. because of their incarceration,
they may be under constraints which
could affect their ability to make a truly
voluntary and uncoerced decision
whether or not to participate in such
activities.
§46.403 Definitions.
As used in this subpart :
'a) "Secretary" means the Secretary
of Health. Education, and Welfare or
any other officer or employee of the De-
partment of Health, Education, and Wel-
fare to whom authority has been dele-
gated.
(b) "Prisoner" means any individual
involuntarily confined in a penal insti-
tution. The term Is intended to encom-
pass individuals sentenced to such an in-
stitution under a criminal or civil statute
and also individuals detained to other
facilities by virtue of statutes or commit-
ment procedures which provide alterna-
tives to criminal prosecution or incar-
ceration in a penal institution.
§ 46,404 Additional duties of llie orsa-
pns.
volvcd.
»lu
(a) In addition to the responsibilities
prescribed for such committees under
Subpart A of this part, the applicant's or
offeror's organizational review commit-
tee shall, with respect to activities
covered by this subpart, carry out tlie
following additional duties:
(1) Determine that there will be no
undue Inducements to participation by
prisoners as subjects in the activity,
taking into accoimt such factors as
whether the earnings, living conditions,
medical care, quality of food, and
amenities offered to participants in the
activity would be better than those gen-
erally available to the prisoners;
i2i Determine that ii> all aspects of
the activity would be appropriate for per-
formance on nonprisoners. or (ii) the
activity involves negligible risk to the
subjects and is for the purpose of study-
ing the effects of incarceration on such
subjects;
(3) Determine that the application or
proposal contains adequate procedures
for selection of subjects, securing con-
sents, monitoring continued subject par-
ticipation, and assuring withdrawal with-
KDERAL REGISTER, VOL. 39, NO 165 — FRIDAY, AUGUST 23, 1974
PROPOSED RULES
3063
out prejudice, tn accordance with
§ 46-405 of ttiis sut^art;
(4) Determine that rates of remunCTa-
tion are consistent with the anticipated
duration of the activity, but not In excess
of that paid for other employment g^en-
erally available to inmates of the facility
in question, and that withdrawal from
the project for medical reasons will not
result in loss of anticipated remunera-
tion; and
(5) Carry out such othei- responsibili-
ties as may be assigned by the Secretary,
(b) AppUcants or offerors seeking sup-
port for activities covered by this sub-
part must provide for the designation of
an organizational review committee, sub-
ject to approval by the Secretary, where
no such committee has been established
under Subpart A of this part.
(c) No award may be issued until the
applicant or offeror has certified to the
Secretary that the organizational review
committee has made the determinations
required under paragraph Ca) of tliis
section.
(a) Except as provided in paragraph
(c> of this section, no activity covered
by this subpart may be supported unless
the applicant or offeror has provided an
assiirance acceptable to the Secretary
that it will establish a consent commit-
tee (as provided for in the application
or offer and approved by the organiza-
tional review committee and the Secre-
tary) for each such activity, to oversee
the actual process by which individual
subjects are selected and their consents
secured, to monitor the progress of the
activity (including visits to the activity
site on a regular basis) and the continued
■willingness of the subjects to participate,
to intervene on behalf of one or more sub-
jects if conditions warrant, and to carry
out such other duties as the Secretary
may prescribe. The duties of the consent
committee may include:
(1) Participation in the actual process
by which individual subjects are selected
and their consents secm-ed to assure that
all elements of a legally effective in-
formed consent, as outlined in section
46.3 of this part, are satisfied. Depend-
ing on what may be prescribed in the
application or offer approved by the Sec-
retary, this might require approval by
the conmiittee of each individual's par-
ticipation as a subject in the activity or
it might simply call for verification te.g.,
through sampling) that procedures pre-
scribed in the approved application or
offer are being followed.
(2) Monitoring the progress of the ac-
tivity and the continued willingness of
subjects to participate. Depending on
what may be prescribed in the applica-
tion or offer approved by the Secretary,
this might include: visits to the activity
site, identification of one or more com-
mittee members who would be available
for consultation with subjects at the sub-
jects' request, continuing evaluation to
determine if any unanticipated risks have
arisen and that any such risks are com-
municated to the subjects, periodic con-
tact with the subj ects to ascertain
whether they remain willing to continue
in the study, providing for the with-
drawal of any subjects who wish to do
so. and authority to terminate participa-
tion of one or more subjects with or
uithout their consent where conditions
warrant.
(b) The size and composition of the
consent committee must be approved by
the Secretary, taking into account such
factors as: (1) the scope and nature of
the activity; (2) the particular subject
groups involved; (3) whether the mem-
bership has been so selected as to be
competent to deal with the medical, legal,
social, and ethical issues involved in the
activity; (4) whether the committee in-
cludes a prisoner or a representative of
an orgamzation having as a primai-y
concern protection of prisoners' inter-
ests: (5) whether the committee includes
suf&cient members who are imaffillated
with the applicant or offeror apart from
membership on the committee; and <6)
whether the committee includes sufficient
members who are not engaged in re-
search, development, or related activities
involving human subjects. The commit-
tee shall establish rules of procedure for
carrj-ing out its functions and shall con-
duct its business at convened meetings,
with one of its members designated as
chairperson.
fc) Where a particular activity in-
volves negligible risk to the subjects, an
applicant or offeror may request the
Secretary to modify or waive the require-
ment in paragraph (a) of this section. If
the Secretary finds that the risk is indeed
negligible and other adequate controls
are provided, he may grant the request
In whole or in part.
§ 46.406 Special rcslrulions.
Persons detained in a correctional fa-
cility pending arraignment, trial, or sen-
tencing or in a hospital facility for pre-
arraignment, pre-trial, or pre-sentence
diagnostic observation are excluded from
participation in activities covered by this
subpart, unless (a) the organizational re-
view committee finds that the particular
activity involves only negligible risk to
the subjects and (b) the activity is thera-
peutic in intent or relates to the nature
of their confinement.
Activities to which this subpart is ap-
plicable, to be conducted outside the
United States, are subject to the require-
ments of this subpart, except that the
consent procedures specified herein may
be modified if it is shovra to the satisfac-
tion of the Secretary that such proce-
dures, as modified, are acceptable under
the laws and regulations of the country in
which the activities are to be performed
and that they comply udth the require-
ments of Subpart A of this part.
Subpart E — Additional Protections Pertain-
ing to Activities Involving the Institu-
tionalized Mentally Disabled as Subjects
§ 46.501 Applicability.
(a) The regulations in this subpart
are applicable to all Department of
Health, Education, and Welfare grants
and contracts supporting research, de-
velopment, and related activities involv-
ing the Institutionalized mentally dis-
abled as subjects.
(b) Nothing in this subpart shall be
construed as indicating that comphance
with the procedures set forth herein will
necessarily result In a legally effective
consent under applicable State or local
law to a subject's participation in such
an activity; nor in particular does it ob-
viate the need for court approval of such
participation where court approval is re-
quired under applicable State or local law
in order to obtain a legally effective
consent.
(c) The requirements of this subpart
are in addition to those imposed under
the other subparts of this part;.
§ 46.302 Purpose.
It is the purpose of this subpart to
provide additional safeguai'ds for the
protection of the institutionalized men-
tally disabled involved in activities to
which this subpart is applicable, inas-
much as: fa) they are confined In an
institutional setting where their freedom
and rights are potentially subject to lim-
itation; (b) they may be unable to com-
prehend sufficient information to give
an informed consent, as that term is de-
fined in §46.103; and (c) they may be
legally incompetent to consent to their
participation in such activities.
§ 16.503 Definitions.
As used in this subpart:
(a) "Secretary" means the Secretary
of Health, Education, and Welfare or any
other officer or employee of the Depart-
ment of Health. Education, and Welfare
to whom authority has been delegated.
(b) "Mentally disabled" includes those
institutionalized individuals who are
mentally ill, mentally retarded, emotion-
ally disturbed, or senile, regardless of
their legal status or basis of institutional-
ization.
(c' "Institutionalized" means con-
fined, whether by voluntary' admission or
involuntary commitment, m a residen-
tial institution for the care or treatment
of the mentally disabled.
(d) "Institutionalized mentally dis-
abled individuals" includes but is not
limited to patients in pubhc or private
mental hospitals, psychiatric patients in
general hospitals, inpatients of commu-
nity mental health centers, and mentally
disabled individuals who reside in half-
way houses or nursing homes.
§ 46.504 Aciivilics involvins the inslilu-
tionalizcd mentally disabled.
Institutionalized mentally disabled in-
dividuals may not be included in an
activity covered by this subpart unless:
(a) The proposed activity is related
to the etiology, pathogenesis, prevention,
diagnosis, or treatment of mental dis-
ability or the management, training, or
rehabilitation of the mentally disabled
and seeks information which cannot be
obtained from subjects who are not insti-
tutionalized mentally disabled;
fb) The individual's legally effective
Informed consent to participation In the
No. 165— Pt. III-
FEDERAt REGISTER, VOL. 39, NO. 165— FRIDAY, AUGUST 23, 1974
30656
PROPOSED RULES
activity or, where the individual is le-
gally incompetent, the Informed coasent
of a representative with legal authority
so to consent on behalf of the Individual
has been obtained; and
(CI Tlie individual's assent to such
participation has also been secured, when
in the judgment of the consent committee
he or she has sufficient mental capacity
to understand what Is proposed and to
express an opinion as to his or her par-
ticipation.
§ 16.505 AdHiiion:)! duli
thr
nuli^
of the orgo-
inilloe uhrrc
nienlully dU-
(a) In addition to the responsibilities
prescribed for such committees under
Subpart A of this part, the applicant's or
offeror's organizational review commit-
tee shall, with respect to activities cov-
ered by this subpart, carry out the follow-
ing additional duties:
(1) Determine that all aspects of the
activity meet the requirements of § 46.50
<a) of this subpart:
<2> Determine that there will be no
imdue Inducements to participation by
individuals as subjects in the activity,
taking into account such factors as
whether the earnings. living conditions,
medical care, quality of food, and ameni-
ties offered to participants in the activity
would be better than those generally
available to the mentally disabled at the
Institutions;
(3) Determine that the application or
proposal contains adequate procedures
for selection of subjects, securing con-
sents, protecting confidentiality, and
monitoring continued subject participa-
tion, in accordance with § 46.506 of this
subpart; and
(4) Carry out such other responsibil-
ities as may be assigned by the Secretary.
<b) Applicants or offerors seeking
support for activities covered by this
subpart must provide for the designation
of an organizational review committee,
subject to approval by the Secretary,
where no such committee has been es-
tablished under Subpart A of this part,
(c) No award may be issued until the
applicant or offeror has certified to the
Secretary that the organizational review
committee has made the determinations
required under paragraph (a) of this
section.
(a) Except as provided in paragi-aph
<c) of tills section, no activity covered by
this subpart may be supported unless the
applicant or offeror has provided a sepa-
rate assurance acceptable to the Secre-
tary that it will establish a consent
committee (as provided for in tlie appli-
cation or offer and approved by the orga-
nizational review committee and the sec-
retary) for each such activity, to oversee
the actual process by which individual
.■subjects are selected and consents re-
quired by this subpart are secured, to
monitor the progress of the activity (in-
cluding visits to the activity site on a
regular basis) and the continued willing-
ness of the subjects to participate, to in-
tervene on behalf of one or more subjecJ^s
if conditions warrant, and to carry oui
such other duties as the Secretaiy may
prescribe. The duties of the consent com-
mittee may include:
( 1 1 Participation in the actual process
by whicla individual subjects are selected
and their consents secured to assure that
all elements of a legally effective in-
foiTned consent, as outlined in g 46,3, arc
satisfied. Depending on what may be pre-
scribed in the application or offer ap-
proved by the Secretary, this might re-
quire approval by the committee of each
individual's participation as a subject in
the activity or it might simply call for
verification (eg. through sampling i that
procedures prescribed in the approved
application or offer are being followed.
(2> Monitoring the progress of the
activity and the continued willingness
of subjects to participate. Depending on
what may be prescribed in the applica-
tion or offer approved by the Secretary,
this might include: visits to the activity
site, identification of one or more com-
mittee members who would be available
for consultation with subjects at the
subjects' request, continuing evaluation
to (letermine if any unanticipated risks
have arisen and that any such risks are
communicated to the subjects, periodic
contact with the subjects to ascertain
whether they remaip willing to continue
in the study, providing for the with-
drawal of any subjects who wish to do so,
and authority to terminate participa-
tion of one or more subjects with or
without their consent where conditions
warrant.
(b) The size and composition of the
consent committee must be approved by
tlie Secretary, taking into account such
factors as: (1) the scope and nature of
the activity; (2» the particular subject
groups involved; (3) whether the mem-
bership has been so selected as to be
competent to deal with the medical,
legal, social, and ethical issues involved
in the activity; (4) whether the com-
mittee includes sufficient members who
are unaffiliated with the applicant or
offeror apart from membership on the
committee; and (5i whether the com-
mittee includes sufficient members who
are not engaged in research, develop-
ment, or related activities involving
human subjects. The committee shall
establish rules of procedure for carrying
out its functions and shall conduct its
business at convened meetings, with one
of Its members designated as chair-
person.
(c) Where a particular activity in-
volves negligible risk to the subjects, an
applicant or offeror may request the Sec-
retary to modify or waive the rer.uire-
ment in paragraph (a' of this section. If
the Secretary finds that the risk is in-
deed negligible and other adequate con-
trols are provided, he may grant the re-
quest in whole or in part.
Activities to which this subpart is ap-
plicable, to be conducted outside the
United States, are subject to the require-
ments of this subpart, except tliat the
consent procedures specified herein may
be modified If it is shown to the satis-
faction of the Secretary that such proce-
dures, as modified, are acceptable 'onder
tile laws and regulations of the country
in which the activities are to be per-
foimed and that they comply with the
requirements of Subpart A of this part.
Subpart F — General Provisions
§ 16.601 Applicabiliiy.
Sections 46,602 through 46.606 are ap-
plicable to all grant or contract sup-
ported activities covered by this part.
§ 46.602 Multiple consent coinmiUet! rc-
Where an application or proposal
would involve human subjects covered
by more than one consent committee
requirement imposed under this part,
upon approval by the Secretary, these
multiple requirements may be satisfied
tlirough use of a single consent commit-
tee appropriately constituted to take ac-
count of the nature of the subject group.
§ 16.603 Orpanizalion's records; confi-
denlialily.
(a) Copies of all documents presented
or required for initial and continuing re-
view by the organization's review com-
mittee or consent committee, such as
committee minutes, records or subjects'
consent, transmittals on actions, in-
structions, and conditions resulting from
committee deliberations addressed to the
activity director, are to be retained by
the organization, subject to the terms
and conditions of grant and contract
awards.
(bt Except as otherwise provided by
law, infonnation In the records or pos-
session of an organization acquired in
connection with an activity covered by
this part, which information refers to or
can be identified with a particular sub-
ject, may not be disclosed except:
lU With the consent of the subject
or his legally authorized representative;
or
(2) As may be necessai-y for the Sec-
retai-y to- carry out his responsibilities
under this part in the exercise of over-
sight for the protection of such subject
or class of subjects.
§ 16.60 ^ Reports.
Each organization with an approved
assurance shall provide the Secretary
with such reports and other Information
as the Secretary may from time to time
prescribe.
§16.605 Early termination of awurd^:
evaliiiilion of subsequent applicii-
lions.
(a) If, in the judgment of the Secre-
tary, an organization has failed ma-
terially to comply with the terms of this
policy with respect to a particular De-
partment of Health. Education, and
Welfare grant or contract, he may requre
that said grant or contract be terminated
or suspended In the manner prescribed
in applicable grant or procurement
regulations.
FEDERAL REGISTER, VOL 39, No. 165— FRIDAY, AUGUST 23, 1974
PROPOSED RULES
30G57
(b> In evaluating pTopoBais or appli-
cations tor support of activities covered
by this part, the Secretary may take Into
account. In addition to afl other eligibil-
ity requirements and program criteria,
such factors as: <1) whether the offeror
or applicant has been subject to a ter-
mination or suspension under paragraph
(a) of this section. (2) whether the of-
feror or applicant or the person who
would direct the scientific and technical
aspects of an activity has in the judg-
ment of the Secretary failed materially
to discharge his, her, or its responsibility
for the protection of the rights and wel-
fare of subjects and (3) whether, where
past deficiencies have existed in dis-
charging such responsibility, adequate
steps have in the judgment of the Secre-
tary been talcen to eliminate these
deficiencies.
§ 46.606 Condilions.
The Secretary may with respect to
any grant or contract or any class of
grants or contracts impose additional
conditions prior to or at the time of any
award when in his Judgment such condi-
tions are necessary for the protection of
human subjects.
§ 16.607 Aclivilics conduclcd b^ De-
piirtincnt employees.
The regulations of this part (except
for this subpart) are applicable as well
to all research, development, and related
activities conducted by employees of the
Department of Health, Education and
Welfare, except that: (a) subpart C is
applicable only to biomedical research,
development, and related activities and
(b) each agency head may adopt such
procedural modificatlonE as may be ap-
propriate from an administrative stand-
point.
IFR Doc.74-19300 FUed 8-20-74:8:46 am]
RDHtAI IEOISTEI^ vol. M, No, 1«5— FRIDAY, AUGUST 23, l«74
DEPARTMENT OF HEALTH,
EDUCATION, AND WELFARE
Office of the Secretary
[ 45 CFR Port 46 ]
PROTECTION OF HUMAN SUBJECTS
Correction of Preamble to Proposed Policy
In the August 23, 1974 Issue of the
Federal Register (39 FR 30548), the
Department of Health. Education, and
Welfare published a notice of proposed
rulemaking governing research, develop-
ment, and related activities, supported
by the Department, Involving the fetus,
abortus, pregnant women, in vitro fer-
tilization, prisoners, and the Institution-
alized mentally disabled.
After publication the following errors
were noted in the preamble to the pro-
posed rulemal^ing: ---^
(1) The Initial three paragraphs of
Section C on page 30650 fail to indicate
that, because of the Department's con-
cern about the ethical Issues surrounding
In vitro fertilization (whether or not
Implantation is contemplated), the pro-
posed rulemaking would require that all
activities Involving In vitro fertilization
be reviewed by the Ethical Advisory
Board prior to funding. In order to malce
clear this concern these paragraphs have
been revised to read as follows:
C. A number of respondents recom-
mended that the policy governing in
vitro fertilization be strengthened, on
the one hand, or libeialized, on the other.
The Department has considered these
recommendations, and concluded that
while it is necessary to impose certain
restraints, it is contrary to the interests
of society to set permanent restrictions
on research which are based on the suc-
cesses and limitations of current tech-
nology. Therefore, the Department would
expect the Ethical Advisory Board, which
must review all applications involving
In vitro fertilization (whether or not im-
plantation is contemplated) to weigh,
with respect to specific proposals, the
state of the art, legal issues, community
standards, and the availability of guide-
lines to govern each research situation.
In sum, If there is a possibility that the
conceptus might be sustained in vitro
beyond the earliest stages of develop-
ment, the Ethical Advisory Board Is to
consider this possibility, and determine
what guidelines should govern decisions
affecting that fetus, if the research Is to
be permitted. If, on the other hand,
implantation is attempted and achieved,
then regulations governing the fetus in
utero shall apply,
(2) Several sentences were inadvert-
ently omitted from the first and second
paragraphs of the discussion of "Viability
of the Fetus" In the first column on page
30651. These sentences are now Inserted
and as revised, the paragraphs read es
follows :
2. "Viability of the Fetus." Some re-
spondents suggested specific criteria such
as bli'th weight, crown-inimp length, or
gestational age, similar to those used In
England, such criteria to be reviewed and
reissued periodically by the Department.
It was emphasized that the use of such
objective criteria might simplify prob-
lems involved in determining what types
of research might be permissible. Some
respondents urged that presence of fetal
heartbeat be definitive (whether or not
there is respiration) while others urged
that Identifiable cortical activity be
specified as an alternative sign of via-
bility. Others objected strenuously to
any distinction as to the nature of fetal
life, holding that the physician's obli-
gation should be the same to any fetus
regardless of weight, size, or age of
gestation.
The Department, having reviewed
the.se comments, concludes that the dis-
tinction between a viable and a nonr
viable fetus Ls both valid and meaningful.
At the same time, the Department does
not believe that the use of weight, size,
gestaliona! age and or cortical activity
is a valid substitute for the judgment of
a physician, particularly in view of the
wide variation in the facihties and arts
available to him both in this coimtry and
abroad. The Department further con-
cludes that the issue of viability is a
function of technological advance [see
§46.303'e) of the regulations], and
therefore must be decided with reference
to the medical realities of the present
time, while reserving the right to rede-
fine the parameters as conditions
warrant."
(3) Section H on page 30651 incor-
rectly implies that, under the proposed
rulemaliing, fetuses for which abortion
is contemplated may be placed at greater
risk than fetuses in general. In tact,
however, as is stated already in section
F on page 30651, the proposed rulemaking
bans the undertaking of research, devel-
opment, or related activities involvin.i; the
fetus prior to the commencement of the
abortion procedure, at which point the
question of risk to the fetus is no longer
an issue. Such activities which are per-
mitted under the regulations would be
reviewed by the Ethical Advisory Board
prior to funding- Section H should there-
fore be deleted and section I on the same
page relettered section H.
Dated: October 21. 1974.
Caspar W. Weinberger,
Secretary.
[FR Doc.74-24994 Filed 10-24-74:8:45 am]
FEDERAL REGIHEI, VOL 39, NO. 208 — FRIDAY. OCTOBER 25, 1974
•{"U.S. GOVERNMENT PRINTING OFFICE: 1976-622-094
q.
'%^^
\ '<^ # 'V *>
^.. -x^"^ \.. J
«*' ,**^ X.
\rj/ \ *™.^ / \ ^j / X **^" / \ ^^ / \ '^-'
'^ ^ ^% "'^ ^ /£^^ ^' '^ -/3\ ^ -** i^ >> ^* /I*. ^> -^'
. ./ .g,\ ..^%3.,\ ..^-.^\ ..*%^,\
-^ %.
^"^ ^^% \ -^^^
m.
^^.
%
'JK. ,<?> -v. ^ '/C x!> -V. v'V V, i^ •'v
^v^ /•■ \ -^'^^^
^. '^<- ^^ #!». \
\ 4
% ^
^/\^/\^/\^/\^y^. ^
V ^«- ^"Z's
K "^"V
#
M
NMH
U^ AmazinsRese
'eso&fch.
Amazing Help.
http.V/nihlibrary.nfh.gov
10 Center Drive
Bethesda, MD 20892-1150
301-496-1080
^^-"^
^■^
J^^
•/
/\
*>. "^ ..-.^^
^^
/
^««
^Z'
Afs-
\ / .^*
^^ #
^^^ .^^ \ ^-^^" / \ W / \ ^S^ / \ ^^ / ^^
a \ :
■ ■ - j>^\B
a
X ^^ .*"* \.. «* .^-^ V *^ #-^ V ^* .^^ ^^
a;
^1 . .
-^ / \
/ ^-^^ \ / ^
\ /.£»%% ^
•^ \
/ \
^/
^^ \ /
A '\ ^^ ^"^* \ / ^^
"^x J!^ <^-SM \-
■<'% V-9S
^1
^> >^
/%^^ / .©/^^ / ^^"^^ >^ i^V^^ ^
3 1496 00629 7439
'CU'jU
m\
Live Music
Archive
Librivox
Free Audio
Metropolitan Museum
Cleveland
Museum of Art
Internet
Arcade
Console Living Room
Open Library
American
Libraries
TV News
Understanding
9/11